bims-glucam 2020-11-15 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2020–11–15
37 papers selected by
Sreeparna Banerjee, Middle East Technical University

NDRG2 ablation reprograms metastatic cancer cells towards glutamine dependence via the induction of ASCT2.
A second Warburg-like effect in cancer metabolism: The metabolic shift of glutamine-derived nitrogen: A shift in glutamine-derived nitrogen metabolism from glutaminolysis to de novo nucleotide biosynthesis contributes to malignant evolution of cancer.
Anticancer Properties of Lobetyolin, an Essential Component of Radix Codonopsis (Dangshen).
Myeloma Cells Deplete Bone Marrow Glutamine and Inhibit Osteoblast Differentiation Limiting Asparagine Availability.
Inhibition of Glutamine Utilization Synergizes with Immune Checkpoint Inhibitor to Promote Antitumor Immunity.
Glutamate metabolism in a human intestinal epithelial cell layer model.
Upregulation of Antioxidant Capacity and Nucleotide Precursor Availability Suffices for Oncogenic Transformation.
Metabolic pathways underlying GATA6 regulating Trastuzumab resistance in Gastric Cancer cells based on untargeted metabolomics.
Lysosomal Acid Lipase Deficiency Controls Treg and Breg Homeostasis in the Lymph Nodes of Mice with Human Cancer Xenotransplants.
Endogenous production of glutamine and plasma glutamine concentration in critically ill patients.
Metabolic Cancer-Macrophage Crosstalk in the Tumor Microenvironment.
Dyslipidemia, insulin resistance, and impairment of placental metabolism in the offspring of obese mothers.
Insulin Promotes Mitochondrial Respiration and Survival through PI3K/AKT/GSK3 Pathway in Human Embryonic Stem Cells.
A translational program that suppresses metabolism to shield the genome.
SLC7A11/xCT in cancer: biological functions and therapeutic implications.
Metastatic Breast Cancer and Pre-Diagnostic Blood Gene Expression Profiles-The Norwegian Women and Cancer (NOWAC) Post-Genome Cohort.
Increased mTOR activity and metabolic efficiency in mouse and human cells containing the African-centric tumor-predisposing p53 variant Pro47Ser.
The high-energy transition state of the glutamate transporter homologue GltPh.
Regulation and Function of Autophagy in Pancreatic Cancer.
Urine metabolomics of rats with chronic atrophic gastritis.
Amino Acid Starvation Sensitizes Resistant Breast Cancer to Doxorubicin-Induced Cell Death.
Cancer cell metabolic reprogramming: a keystone for the response to immunotherapy.
Discovery and optimization of withangulatin A derivatives as novel glutaminase 1 inhibitors for the treatment of triple-negative breast cancer.
Botanical sulfane sulfur donors inhibit ferroptotic cell death caused by the depletion of cysteine.
Crosstalk Between Skeletal Muscle and Immune System: Which Roles Do IL-6 and Glutamine Play?
Can natural selection and druggable targets synergize? Of nutrient scarcity, cancer, and the evolution of cooperation.
Mitochondria and nucleus cross-talk: Signaling in metabolism, apoptosis, and differentiation, and function in cancer.
Sorafenib induces mitochondrial dysfunction and exhibits synergistic effect with cysteine depletion by promoting HCC cells ferroptosis.
Plasma free amino acid profiling as metabolomic diagnostic and prognostic biomarker in paediatric cancer patients: a follow-up study.
Frizzled-7 Identifies Platinum Tolerant Ovarian Cancer Cells Susceptible to Ferroptosis.
Role of different immune cells and metabolic pathways in modulating the immune response in pancreatic cancer (Review).
Regulation of PD-L1 expression in K-ras-driven cancers through ROS-mediated FGFR1 signaling.
Nucleotide de novo synthesis increases breast cancer stemness and metastasis via cGMP-PKG-MAPK signaling pathway.
Crosstalk between mechanotransduction and metabolism.
Metabolic regulation of innate immune cell phenotypes during wound repair and regeneration.
Molecular mechanisms of cancer cachexia‑induced muscle atrophy (Review).
Cancer Alters the Metabolic Fingerprint of Extracellular Vesicles.

Int J Biol Sci. 2020 ;16(16): 3100-3115

NDRG2 ablation reprograms metastatic cancer cells towards glutamine dependence via the induction of ASCT2.

Mingchao Ding, Xin Bu, Zhehao Li, Haokun Xu, Lin Feng, Junbi Hu, Xinxin Wei, Jiwei Gao, Yanyan Tao, Bolei Cai, Yanpu Liu, Xuan Qu, Liangliang Shen.

  Background: Metastasis is the most common cause of lethal outcome in various types of cancers. Although the cell proliferation related metabolism rewiring has been well characterized, less is known about the association of metabolic changes with tumor metastasis. Herein, we demonstrate that metastatic tumor obtained a mesenchymal phenotype, which is obtained by the loss of tumor suppressor NDRG2 triggered metabolic switch to glutamine metabolism. Methods: mRNA-seq and gene expression profile analysis were performed to define the differential gene expressions in primary MEC1 and metastatic MC3 cells and the downstream pathways of NDRG2. NDRG2 regulation of Fbw7-dependent c-Myc stability were determined by immunoprecipitation and protein half-life assay. Luciferase reporter and ChIP assays were used to determine the roles of Akt and c-Myc in mediating NDRG2-dependent regulation of ASCT2 in in both tumor and NDRG2-knockout MEF cells. Finally, the effect of the NDRG2/Akt/c-Myc/ASCT2 signaling on glutaminolysis and tumor metastasis were evaluated by functional experiments and clinical samples. Results: Based on the gene expression profile analysis, we identified metastatic tumor cells acquired the mesenchymal-like characteristics and displayed the increased dependency on glutamine utilization. Further, the gain of NDRG2 function blocked epithelial-mesenchymal transition (EMT) and glutaminolysis, potentially through suppression of glutamine transporter ASCT2 expression. The ASCT2 restoration reversed NDRG2 inhibitory effect on EMT program and tumor metastasis. Mechanistic study indicates that NDRG2 promoted Fbw7-dependent c-Myc degradation by inhibiting Akt activation, and subsequently decreased c-Myc-mediated ASCT2 transcription, in both tumor and NDRG2-knockout MEF cells. Supporting the biological significance, the reciprocal relationship between NDRG2 and ASCT2 were observed in multiple types of tumor tissues, and associated with tumor malignancy. Conclusions: NDRG2-dependent repression of ASCT2 presumably is the predominant route by which NDRG2 rewires glutaminolysis and blocks metastatic tumor survival. Targeting glutaminolytic pathway may provide a new strategy for the treatment of metastatic tumors.

Keywords:  ASCT2; EMT; NDRG2; c-Myc; glutaminolysis; mucoepidermoid carcinoma

DOI:  https://doi.org/10.7150/ijbs.48066
Bioessays. 2020 Nov 09. e2000169

A second Warburg-like effect in cancer metabolism: The metabolic shift of glutamine-derived nitrogen: A shift in glutamine-derived nitrogen metabolism from glutaminolysis to de novo nucleotide biosynthesis contributes to malignant evolution of cancer.

Manabu Kodama, Keiichi I Nakayama.

  Carbon and nitrogen are essential elements for life. Glucose as a carbon source and glutamine as a nitrogen source are important nutrients for cell proliferation. About 100 years ago, it was discovered that cancer cells that have acquired unlimited proliferative capacity and undergone malignant evolution in their host manifest a cancer-specific remodeling of glucose metabolism (the Warburg effect). Only recently, however, was it shown that the metabolism of glutamine-derived nitrogen is substantially shifted from glutaminolysis to nucleotide biosynthesis during malignant progression of cancer-which might be referred to as a "second" Warburg effect. In this review, address the mechanism and relevance of this metabolic shift of glutamine-derived nitrogen in human cancer. We also examine the clinical potential of anticancer therapies that modulate the metabolic pathways of glutamine-derived nitrogen. This shift may be as important as the shift in carbon metabolism, which has long been known as the Warburg effect.

Keywords:  de novo nucleotide biosynthesis; glutamine metabolism; glutaminolysis; meta-analysis; small cell lung cancer

DOI:  https://doi.org/10.1002/bies.202000169
Nat Prod Bioprospect. 2020 Nov 07.

Anticancer Properties of Lobetyolin, an Essential Component of Radix Codonopsis (Dangshen).

Christian Bailly.

  Lobetyolin (LBT) is a polyacetylene glycoside found in diverse medicinal plants but mainly isolated from the roots of Codonopsis pilosula, known as Radix Codonopsis or Dangshen. Twelve traditional Chinese medicinal preparations containing Radix Codonopsis were identified; they are generally used to tonify spleen and lung Qi and occasionally to treat cancer. Here we have reviewed the anticancer properties of Codonopsis extracts, LBT and structural analogs. Lobetyolin and lobetyolinin are the mono- and bis-glucosylated forms of the polyacetylenic compound lobetyol. Lobetyol and LBT have shown activities against several types of cancer (notably gastric cancer) and we examined the molecular basis of their activity. A down-regulation of glutamine metabolism by LBT has been evidenced, contributing to drug-induced apoptosis and tumor growth inhibition. LBT markedly reduces both mRNA and protein expression of the amino acid transporter Alanine-Serine-Cysteine Transporter 2 (ASCT2). Other potential targets are proposed here, based on the structural analogy with other anticancer compounds. LBT and related polyacetylene glycosides should be further considered as potential anticancer agents, but more work is needed to evaluate their efficacy, toxicity, and risk-benefit ratio.

Keywords:  Cancer therapy; Glutamine metabolism; Lobetyolin; Mechanism of action; Molecular target; Natural products; Polyacetylene glycoside; Terpenoids

DOI:  https://doi.org/10.1007/s13659-020-00283-9
Cancers (Basel). 2020 Nov 05. pii: E3267. [Epub ahead of print]12(11):

Myeloma Cells Deplete Bone Marrow Glutamine and Inhibit Osteoblast Differentiation Limiting Asparagine Availability.

Martina Chiu, Denise Toscani, Valentina Marchica, Giuseppe Taurino, Federica Costa, Massimiliano G Bianchi, Roberta Andreoli, Valentina Franceschi, Paola Storti, Jessica Burroughs-Garcia, Rosa Alba Eufemiese, Benedetta Dalla Palma, Nicoletta Campanini, Eugenia Martella, Cristina Mancini, Jixiu Shan, Michael S Kilberg, Giovanna D'Amico, Erica Dander, Luca Agnelli, Giancarlo Pruneri, Gaetano Donofrio, Ovidio Bussolati, Nicola Giuliani.

  Multiple myeloma (MM) cells consume huge amounts of glutamine and, as a consequence, the amino acid concentration is lower-than-normal in the bone marrow (BM) of MM patients. Here we show that MM-dependent glutamine depletion induces glutamine synthetase in stromal cells, as demonstrated in BM biopsies of MM patients, and reproduced in vitro by co-culturing human mesenchymal stromal cells (MSCs) with MM cells. Moreover, glutamine depletion hinders osteoblast differentiation of MSCs, which is also severely blunted by the spent, low-glutamine medium of MM cells, and rescued by glutamine restitution. Glutaminase and the concentrative glutamine transporter SNAT2 are induced during osteoblastogenesis in vivo and in vitro, and both needed for MSCs differentiation, pointing to enhanced the requirement for the amino acid. Osteoblastogenesis also triggers the induction of glutamine-dependent asparagine synthetase (ASNS), and, among non-essential amino acids, asparagine rescues differentiation of glutamine-starved MSCs, by restoring the transcriptional profiles of differentiating MSCs altered by glutamine starvation. Thus, reduced asparagine availability provides a mechanistic link between MM-dependent Gln depletion in BM and impairment of osteoblast differentiation. Inhibition of Gln metabolism in MM cells and supplementation of asparagine to stromal cells may, therefore, constitute novel approaches to prevent osteolytic lesions in MM.

Keywords:  SNAT2; asparagine; asparagine synthetase; bone disease; glutaminase; glutamine; glutamine synthetase; multiple myeloma; osteoblast

DOI:  https://doi.org/10.3390/cancers12113267
Mol Cell. 2020 Oct 27. pii: S1097-2765(20)30722-X. [Epub ahead of print]

Inhibition of Glutamine Utilization Synergizes with Immune Checkpoint Inhibitor to Promote Antitumor Immunity.

Jun-Kyu Byun, Mihyang Park, Seunghyeong Lee, Jae Won Yun, Jaebon Lee, Jae Sun Kim, Sung Jin Cho, Hui-Jeon Jeon, In-Kyu Lee, Yeon-Kyung Choi, Keun-Gyu Park.

  Despite its outstanding clinical success, immune checkpoint blockade remains ineffective in many patients. Accordingly, combination therapy capable of achieving greater antitumor immunity is urgently required. Here, we report that limiting glutamine metabolism in cancer cells bolsters the effectiveness of anti-programmed death ligand-1 (PD-L1) antibody. Inhibition of glutamine utilization increased PD-L1 levels in cancer cells, thereby inactivating co-cultured T cells. Under glutamine-limited conditions, reduced cellular GSH levels caused an upregulation of PD-L1 expression by impairing SERCA activity, which activates the calcium/NF-κB signaling cascade. Consequently, in tumors grown in immunocompetent mice, inhibition of glutamine metabolism decreased the antitumor activity of T cells. In combination with anti-PD-L1, however, glutamine depletion strongly promoted the antitumor efficacy of T cells in vitro and in vivo due to simultaneous increases in Fas/CD95 levels. Our results demonstrate the relevance of cancer glutamine metabolism to antitumor immunity and suggest that co-targeting of glutamine metabolism and PD-L1 represents a promising therapeutic approach.

Keywords:  PD-L1; SERCA; antitumor immunity; glutamine

DOI:  https://doi.org/10.1016/j.molcel.2020.10.015
Amino Acids. 2020 Nov 12.

Glutamate metabolism in a human intestinal epithelial cell layer model.

Ryosei Sakai, Yuri Ooba, Akiko Watanabe, Hidehiro Nakamura, Yasuko Kawamata, Tomoko Shimada, Asuka Takumi, Johannes B van Goudoever, Takahiro Narita.

  Plasma glutamate concentrations are constant despite dynamic changes in diets. Most likely, virtually all the dietary glutamate is metabolized in the gut. The present study investigated permeability and metabolism of dietary glutamate in a Caco-2 intestinal epithelial cell layer model by tracing the fate of [U-13C] or [15N]glutamate added to the apical medium. For comparison, several other labelled essential and non-essential amino acids were tested as well. Almost all the labelled glutamate in the apical medium (98% and 96% at 24 h of the culture, respectively) was incorporated in the cell layer, while it barely appeared at the basolateral side, indicating an almost complete utilization of glutamate. Indeed, the 13C was incorporated into alanine, proline, ornithine, and glutamine, and the 15N was incorporated into alanine, glutamine, ornithine, proline, branched chain amino acids and also found as ammonia indicative of oxidation. In contrast, substantial apical-to-basolateral transport of amino acids (8-85% of uptake) other than glutamate and aspartate was evident in studies using amino acid tracers labelled with 13C, 15N or D. These results suggest that the intestinal epithelial cell monolayer utilizes dietary glutamate which adds to maintaining glutamate homeostasis in the body.

Keywords:  Amino acid; Glutamic acid; Intestinal mucosa; Metabolic barrier; Stable isotope

DOI:  https://doi.org/10.1007/s00726-020-02908-2
Cell Metab. 2020 Nov 06. pii: S1550-4131(20)30535-0. [Epub ahead of print]

Upregulation of Antioxidant Capacity and Nucleotide Precursor Availability Suffices for Oncogenic Transformation.

Yang Zhang, Yi Xu, Wenyun Lu, Jonathan M Ghergurovich, Lili Guo, Ian A Blair, Joshua D Rabinowitz, Xiaolu Yang.

  The emergence of cancer from diverse normal tissues has long been rationalized to represent a common set of fundamental processes. However, these processes are not fully defined. Here, we show that forced expression of glucose-6-phosphate dehydrogenase (G6PD) affords immortalized mouse and human cells anchorage-independent growth in vitro and tumorigenicity in animals. Mechanistically, G6PD augments the NADPH pool by stimulating NAD+ kinase-mediated NADP+ biosynthesis in addition to converting NADP+ to NADPH, bolstering antioxidant defense. G6PD also increases nucleotide precursor levels through the production of ribose and NADPH, promoting cell proliferation. Supplementation of antioxidants or nucleosides suffices to convert immortalized mouse and human cells into a tumorigenic state, and supplementation of both is required when their overlapping metabolic consequences are minimized. These results suggest that normal cells have a limited capacity for redox balance and nucleotide synthesis, and overcoming this limit might represent a key aspect of oncogenic transformation.

Keywords:  G6PD; NAD kinase; NADPH; antioxidants; cancer metabolism; nucleosides; nucleotide synthesis; oncogenic transformation; pentose phosphate pathway; redox regulation

DOI:  https://doi.org/10.1016/j.cmet.2020.10.002
Int J Med Sci. 2020 ;17(18): 3146-3164

Metabolic pathways underlying GATA6 regulating Trastuzumab resistance in Gastric Cancer cells based on untargeted metabolomics.

Jinxia Chang, Qiang Wang, Anup Bhetuwal, Wenhu Liu.

  Trastuzumab has proven its effectiveness in gastric cancer with HER-2 gene-amplification, which has now developed resistance while the mechanism of which is not fully elucidated. Our previous studies demonstrated that the activity of GATA6 binding protein 6 (GATA6) enhanced prominently in trastuzumab resistant gastric cancer cell lines (NCI N87R and MKN45R). In the present study, we further confirmed the re-sensitization to trastuzumab and inhibition of mitochondrial functions of GATA6 knockout sublines (NCI N87R/ΔGATA6 and MKN45R/ΔGATA6). Moreover, we applied untargeted metabolomic profiling to investigate the potential roles of GATA6 in metabolism of NCI N87R and MKN45R. The UPLC system coupled with Q-Exactive Focus Orbitrap mass spectrometry, multivariate in combination with univariate analysis were performed for the screening of differential metabolites between resistant cells and GATA6 knockout sublines. A total of 68 and 59 endogenous metabolites were found to be altered significantly in NCI N87R/ΔGATA6 and MKN45R/ΔGATA6 cells compared with NCI N87R and MKN45R, respectively. Pathway analyses indicated disturbance of metabolic pathways after GATA6 knockout including tricarboxylic acid (TCA) cycle, glycolysis and energy-related amino acid pathways. An integrated proteomics-metabolomics revealed that sub-networks were closely related to TCA cycle, glycolysis, multiple amino acid and nucleotide metabolism. Western blot showed that TCA cycle and glycolysis-related molecules, including PKM, GLS, GLUL and LDHA, were downregulated in GATA6 knockout sublines. Taken together, these findings demonstrate that GATA6 is involved in metabolism reprogramming which might contribute to trastuzumab resistance in gastric cancer.

Keywords:  GATA 6; TCA cycle; gastric cancer; trastuzumab resistance; untargeted metabolomics

DOI:  https://doi.org/10.7150/ijms.50563
Am J Pathol. 2020 Nov 04. pii: S0002-9440(20)30488-0. [Epub ahead of print]

Lysosomal Acid Lipase Deficiency Controls Treg and Breg Homeostasis in the Lymph Nodes of Mice with Human Cancer Xenotransplants.

Xinchun Ding, Ting Zhao, Chih-Chun Lee, Cong Yan, Hong Du.

  Utilization of proper preclinical models accelerates development of immunotherapeutic and the study of the interplay between human malignant cells and immune cells. Lysosomal acid lipase (LAL) is a critical lipid hydrolase that generates free fatty acids and cholesterol. Ablation of LAL suppresses immune-rejection and allows growth of human lung cancer cells in lal-/- mice. In the lal-/- lymph nodes, the percentages of both T regulatory and B regulatory cells (Tregs and Bregs) are increased with elevated expression of PD-L1, IL-10, and decreased expression of IFNγ. In Tregs and Bregs of the lal-/- lymph nodes, levels of enzymes in glucose and glutamine metabolic pathways are elevated. Pharmacologic inhibitor of pyruvate dehydrogenase (PDH), which controls the transition from glycolysis to the citric acid cycle, effectively reduces Treg and Breg elevation in the lal-/- lymph nodes. Blocking the mammalian target of rapamycin (mTOR) or reactivating peroxisome proliferator-activated receptor gamma (PPARγ), an LAL downstream effector, reduces lal-/- Treg and Breg elevation, PD-L1 expression in lal-/- Tregs and Bregs, and improves human cancer cell rejection. Treatment of PD-L1 antibody also reduces Treg and Breg elevation in the lal-/- lymph nodes and improves human cancer cell rejection. These observations conclude that LAL-regulated lipid metabolism is essential to maintain anti-tumor immunity.

Keywords:  Bregs; PD-L1; PPARgamma; Tregs; human cancer cell-derived xenografts; lymph node; lysosomal acid lipase; mTOR; metabolic regulation; tumor animal models

DOI:  https://doi.org/10.1016/j.ajpath.2020.10.007
Clin Nutr ESPEN. 2020 Dec;pii: S2405-4577(20)30202-3. [Epub ahead of print]40 226-230

Endogenous production of glutamine and plasma glutamine concentration in critically ill patients.

Marie Smedberg, Olav Rooyackers, Åke Norberg, Inga Tjäder, Jan Wernerman.

   BACKGROUND: Glutamine plasma concentrations outside the normal range at intensive care unit (ICU) admission are associated with unfavorable outcomes. Based on the hypothesis that hypoglutaminemia in the ICU is the result of an increased utilization of glutamine which cannot be fully met by endogenous production, extra glutamine supplementation has been advocated to ICU patients with hypoglutaminemia. However, it is still unclear whether there is a causal relation between hypo- and hyperglutaminemia and outcomes. Present guidelines advise against supplementation, although there is no evidence available for patients with hypoglutaminemia. The pathophysiology of abnormal glutamine levels and whether glutamine production or glutamine utilization is compromised is largely unknown. Therefore, the aim of this study was to elucidate the relationship between plasma glutamine levels and the endogenous glutamine production in ICU patients.
METHOD: In this observational study, a technique using a small bolus of intravenous glutamine with an isotopic label was used to measure glutamine production.
RESULTS: There was a statistically significant correlation between de novo endogenous production of glutamine (not emanating directly from protein breakdown) and plasma glutamine concentrations in the low and normal range in circulatory stabilized ICU patients (n = 19), R2 = 0.35 (P ≤ 0.01).
CONCLUSION: The predictive value of a low plasma glutamine concentration at ICU admission on outcomes may thus be related to a low endogenous production, which may need to be supplemented in the best interest of this cohort of patients.

Keywords:  Glutamine clearance; Glutamine metabolism; Protein breakdown; Rate of appearance

DOI:  https://doi.org/10.1016/j.clnesp.2020.09.015
Biology (Basel). 2020 Nov 07. pii: E380. [Epub ahead of print]9(11):

Metabolic Cancer-Macrophage Crosstalk in the Tumor Microenvironment.

Kyra E de Goede, Amber J M Driessen, Jan Van den Bossche.

  Tumors consist of a wide variety of cells, including immune cells, that affect tumor progression. Macrophages are abundant innate immune cells in the tumor microenvironment (TME) and are crucial in regulating tumorigenicity. Specific metabolic conditions in the TME can alter the phenotype of tumor-associated macrophages (TAMs) in a direction that supports their pro-tumor functions. One of these conditions is the accumulation of metabolites, also known as oncometabolites. Interactions of oncometabolites with TAMs can promote a pro-tumorigenic phenotype, thereby sustaining cancer cell growth and decreasing the chance of eradication. This review focuses on the metabolic cancer-macrophage crosstalk in the TME. We discuss how cancer cell metabolism and oncometabolites affect macrophage phenotype and function, and conversely how macrophage metabolism can impact tumor progression. Lastly, we propose tumor-secreted exosome-mediated metabolic signaling as a potential factor in tumorigenesis. Insight in these processes may contribute to the development of novel cancer therapies.

Keywords:  TAM; cancer; macrophages; metabolism; oncometabolite; tumor; tumor-associated macrophage

DOI:  https://doi.org/10.3390/biology9110380
J Dev Orig Health Dis. 2020 Nov 13. 1-10

Dyslipidemia, insulin resistance, and impairment of placental metabolism in the offspring of obese mothers.

Matthew Bucher, Kim Ramil C Montaniel, Leslie Myatt, Susan Weintraub, Hagai Tavori, Alina Maloyan.

  Obesity is a chronic condition associated with dyslipidemia and insulin resistance. Here, we show that the offspring of obese mothers are dyslipidemic and insulin resistant from the outset.Maternal and cord blood and placental tissues were collected following C-section at term. Patients were grouped as being normal weight (NW, BMI = 18-24.9) or obese (OB, BMI ≥ 30), and separated by fetal sex. We measured plasma lipids, insulin, and glucose in maternal and cord blood. Insulin resistance was quantified using the HOMA-IR. Placental markers of lipid and energy metabolism and relevant metabolites were measured by western blot and metabolomics, respectively.For OB women, total cholesterol was decreased in both maternal and cord blood, while HDL was decreased only in cord blood, independent of sex. In babies born to OB women, cord blood insulin and insulin resistance were increased. Placental protein expression of the energy and lipid metabolism regulators PGC1α, and SIRT3, ERRα, CPT1α, and CPT2 decreased with maternal obesity in a sex-dependent manner (P < 0.05). Metabolomics showed lower levels of acylcarnitines C16:0, C18:2, and C20:4 in OB women's placentas, suggesting a decrease in β-oxidation. Glutamine, glutamate, alpha-ketoglutarate (αKG), and 2-hydroxyglutarate (2-HG) were increased, and the glutamine-to-glutamate ratio decreased (P < 0.05), in OB placentas, suggesting induction of glutamate into αKG conversion to maintain a normal metabolic flux.Newly-born offspring of obese mothers begin their lives dyslipidemic and insulin resistant. If not inherited genetically, such major metabolic perturbations might be explained by abnormal placental metabolism with potential long-term adverse consequences for the offspring's health and wellbeing.

Keywords:  Maternal obesity; insulin resistance; lipid profile; metabolomics; placental function

DOI:  https://doi.org/10.1017/S2040174420001026
Stem Cell Reports. 2020 Oct 30. pii: S2213-6711(20)30418-5. [Epub ahead of print]

Insulin Promotes Mitochondrial Respiration and Survival through PI3K/AKT/GSK3 Pathway in Human Embryonic Stem Cells.

Zhili Ren, Hui Zhong, Chengcheng Song, Chunhao Deng, Hsun-Ting Hsieh, Weiwei Liu, Guokai Chen.

  Insulin is an essential growth factor for the survival and self-renewal of human embryonic stem cells (hESCs). Although it is best known as the principal hormone promoting glycolysis in somatic cells, insulin's roles in hESC energy metabolism remain unclear. In this report, we demonstrate that insulin is essential to sustain hESC mitochondrial respiration that is rapidly decreased upon insulin removal. Insulin-dependent mitochondrial respiration is stem cell specific, and mainly relies on pyruvate and glutamine, while glucose suppresses excessive oxidative phosphorylation. Pharmacologic and genetic manipulations reveal that continuous insulin signal sustains mitochondrial respiration through PI3K/AKT activation and downstream GSK3 inhibition. We further show that insulin acts through GSK3 inhibition to suppress caspase activation and rescue cell survival. This study uncovers a critical role of the AKT/GSK3 pathway in the regulation of mitochondrial respiration and cell survival, highlighting insulin as an essential factor for accurate assessment of mitochondrial respiration in hESCs.

Keywords:  AKT; GSK3; caspase; cell survival; human embryonic stem cells; insulin; mitochondrial respiration

DOI:  https://doi.org/10.1016/j.stemcr.2020.10.008
Nat Commun. 2020 Nov 13. 11(1): 5755

A translational program that suppresses metabolism to shield the genome.

Nathan C Balukoff, J J David Ho, Phaedra R Theodoridis, Miling Wang, Michael Bokros, Lis M Llanio, Jonathan R Krieger, Jonathan H Schatz, Stephen Lee.

Translatome reprogramming is a primary determinant of protein levels during stimuli adaptation. This raises the question: what are the translatome remodelers that reprogram protein output to activate biochemical adaptations. Here, we identify a translational pathway that represses metabolism to safeguard genome integrity. A system-wide MATRIX survey identified the ancient eIF5A as a pH-regulated translation factor that responds to fermentation-induced acidosis. TMT-pulse-SILAC analysis identified several pH-dependent proteins, including the mTORC1 suppressor Tsc2 and the longevity regulator Sirt1. Sirt1 operates as a pH-sensor that deacetylates nuclear eIF5A during anaerobiosis, enabling the cytoplasmic export of eIF5A/Tsc2 mRNA complexes for translational engagement. Tsc2 induction inhibits mTORC1 to suppress cellular metabolism and prevent acidosis-induced DNA damage. Depletion of eIF5A or Tsc2 leads to metabolic re-initiation and proliferation, but at the expense of incurring substantial DNA damage. We suggest that eIF5A operates as a translatome remodeler that suppresses metabolism to shield the genome.

DOI: https://doi.org/10.1038/s41467-020-19602-2
Am J Cancer Res. 2020 ;10(10): 3106-3126

SLC7A11/xCT in cancer: biological functions and therapeutic implications.

Wenyu Lin, Chaoqun Wang, Guangping Liu, Chao Bi, Xian Wang, Qiyin Zhou, Hongchuan Jin.

Amino acid transporters mediate substrates across cellular membranes and their fine-tuned regulations are critical to cellular metabolism, growth, and death. As the functional component of system Xc-, which imports extracellular cystine with intracellular glutamate release at a ratio of 1:1, SLC7A11 has diverse functional roles in regulating many pathophysiological processes such as cellular redox homeostasis, ferroptosis, and drug resistance in cancer. Notably, accumulated evidence demonstrated that SLC7A11 is overexpressed in many types of cancers and is associated with patients' poor prognosis. As a result, SLC7A11 becomes a new potential target for cancer therapy. In this review, we first briefly introduce the structure and function of SLC7A11, then discuss its pathological role in cancer. We next summarize current available data of how SLC7A11 is subjected to fine regulations at multiple levels. We further describe the potential inhibitors of the SLC7A11 and their roles in human cancer cells. Finally, we propose novel insights for future perspectives on the modulation of SLC7A11, as well as possible targeted strategies for SLC7A11-based anti-cancer therapies.

Keywords: SLC7A11; cancer; cellular metabolism; drug resistance; ferroptosis; redox homeostasis
Front Oncol. 2020 ;10 575461

Metastatic Breast Cancer and Pre-Diagnostic Blood Gene Expression Profiles-The Norwegian Women and Cancer (NOWAC) Post-Genome Cohort.

Einar Holsbø, Karina Standahl Olsen.

  Breast cancer patients with metastatic disease have a higher incidence of deaths from breast cancer than patients with early-stage cancers. Recent findings suggest that there are differences in immune cell function between metastatic and non-metastatic cases, even years before diagnosis. We have analyzed whole blood gene expression by Illumina bead chips in blood samples taken using the PAXgene blood collection system up to two years before diagnosis. The final study sample included 197 breast cancer cases and 197 age-matched controls. We defined a causal directed acyclic graph to guide a Bayesian data analysis to estimate the risk of metastasis associated with the expression of all genes and with relevant sets of genes. We ranked genes and gene sets according to the sign probability for excess risk. Among the screening detected cancers, 82% were without metastasis, compared to 53% of between-screening detected cancers. Among the highest ranking genes and gene sets associated with metastasis risk, we identified plasmacytiod dentritic cell function, the SLC22 family of transporters, and glutamine metabolism as potential links between the immune system and metastasis. We conclude that there may be potentially wide-reaching differences in blood gene expression profiles between metastatic and non-metastatic breast cancer cases up to two years before diagnosis, which warrants future study.

Keywords:  Bayesian data analysis; blood; breast cancer; causal diagrams; immune system; metastasis; transcriptomics

DOI:  https://doi.org/10.3389/fonc.2020.575461
Elife. 2020 11 10. pii: e55994. [Epub ahead of print]9

Increased mTOR activity and metabolic efficiency in mouse and human cells containing the African-centric tumor-predisposing p53 variant Pro47Ser.

Keerthana Gnanapradeepan, Julia I-Ju Leu, Subhasree Basu, Thibaut Barnoud, Madeline Good, Joyce V Lee, William J Quinn, Che-Pei Kung, Rexford Ahima, Joseph A Baur, Kathryn E Wellen, Qin Liu, Zachary T Schug, Donna L George, Maureen E Murphy.

  The Pro47Ser variant of p53 (S47) exists in African-descent populations and is associated with increased cancer risk in humans and mice. Due to impaired repression of the cystine importer Slc7a11, S47 cells show increased glutathione (GSH) accumulation compared to cells with wild -type p53. We show that mice containing the S47 variant display increased mTOR activity and oxidative metabolism, as well as larger size, improved metabolic efficiency, and signs of superior fitness. Mechanistically, we show that mTOR and its positive regulator Rheb display increased association in S47 cells; this is due to an altered redox state of GAPDH in S47 cells that inhibits its ability to bind and sequester Rheb. Compounds that decrease glutathione normalize GAPDH-Rheb complexes and mTOR activity in S47 cells. This study reveals a novel layer of regulation of mTOR by p53, and raises the possibility that this variant may have been selected for in early Africa.

Keywords:  GAPDH; Pro47Ser; Rheb; cancer biology; human; mTOR; metabolism; mouse; p53

DOI:  https://doi.org/10.7554/eLife.55994
EMBO J. 2020 Nov 13. e105415

The high-energy transition state of the glutamate transporter homologue GltPh.

Gerard H M Huysmans, Didar Ciftci, Xiaoyu Wang, Scott C Blanchard, Olga Boudker.

  Membrane transporters mediate cellular uptake of nutrients, signaling molecules, and drugs. Their overall mechanisms are often well understood, but the structural features setting their rates are mostly unknown. Earlier single-molecule fluorescence imaging of the archaeal model glutamate transporter homologue GltPh from Pyrococcus horikoshii suggested that the slow conformational transition from the outward- to the inward-facing state, when the bound substrate is translocated from the extracellular to the cytoplasmic side of the membrane, is rate limiting to transport. Here, we provide insight into the structure of the high-energy transition state of GltPh that limits the rate of the substrate translocation process. Using bioinformatics, we identified GltPh gain-of-function mutations in the flexible helical hairpin domain HP2 and applied linear free energy relationship analysis to infer that the transition state structurally resembles the inward-facing conformation. Based on these analyses, we propose an approach to search for allosteric modulators for transporters.

Keywords:  conformational dynamics; glutamate transporter; single-molecule fluorescence; static disorder; transition-state structure

DOI:  https://doi.org/10.15252/embj.2020105415
Autophagy. 2020 Nov 08.

Regulation and Function of Autophagy in Pancreatic Cancer.

Jingbo Li, Xin Chen, Rui Kang, Herbert Zeh, Daniel J Klionsky, Daolin Tang.

  Oncogenic KRAS mutation-driven pancreatic ductal adenocarcinoma is currently the fourth-leading cause of cancer-related deaths in the United States. Macroautophagy (hereafter "autophagy") is one of the lysosome-dependent degradation systems that can remove abnormal proteins, damaged organelles, or invading pathogens by activating dynamic membrane structures (e.g., phagophores, autophagosomes, and autolysosomes). Impaired autophagy (including excessive activation and defects) is a pathological feature of human diseases, including pancreatic cancer. However, dysfunctional autophagy has many types and plays a complex role in pancreatic tumor biology, depending on various factors, such as tumor stage, microenvironment, immunometabolic state, and death signals. As a modulator connecting various cellular events, pharmacological targeting of nonselective autophagy may lead to both good and bad therapeutic effects. In contrast, targeting selective autophagy could reduce potential side effects of the drugs used. In this review, we describe the advances and challenges of autophagy in the development and therapy of pancreatic cancer.

Keywords:  PDAC; disease; lysosome; macroautophagy; pancreatic ductal adenocarcinoma; tumor

DOI:  https://doi.org/10.1080/15548627.2020.1847462
PLoS One. 2020 ;15(11): e0236203

Urine metabolomics of rats with chronic atrophic gastritis.

Guo-Xiu Zu, Qian-Qian Sun, Jian Chen, Xi-Jian Liu, Ke-Yun Sun, Liang-Kun Zhang, Ling Li, Tao Han, Hai-Liang Huang.

BACKGROUND/AIM: To use liquid chromatography-mass spectrometry (LC-MS) to identify endogenous differential metabolites in the urine of rats with chronic atrophic gastritis (CAG).
MATERIALS AND METHODS: Methylnitronitrosoguanidine (MNNG) was used to produce a CAG model in Wistar rats, and HE staining was used to determine the pathological model. LC-MS was used to detect the differential metabolic profiles in rat urine. Diversified analysis was performed by the statistical method.
RESULTS: Compared with the control group, the model group had 68 differential metabolites, 25 that were upregulated and 43 that were downregulated. The main metabolic pathways were D-glutamine and D-glutamic acid metabolism, histidine metabolism and purine metabolism.
CONCLUSION: By searching for differential metabolites and metabolic pathways in the urine of CAG rats, this study provides effective experimental data for the pathogenesis and clinical diagnosis of CAG.

DOI: https://doi.org/10.1371/journal.pone.0236203
Front Cell Dev Biol. 2020 ;8 565915

Amino Acid Starvation Sensitizes Resistant Breast Cancer to Doxorubicin-Induced Cell Death.

Mark Thomas, Tanja Davis, Theo Nell, Balindiwe Sishi, Anna-Mart Engelbrecht.

  Many clinical trials are beginning to assess the effectiveness of compounds known to regulate autophagy in patients receiving anti-cancer chemotherapy. However, autophagy inhibition, through exogenous inhibitors, or activation, through starvation, has revealed conflicting roles in cancer management and chemotherapeutic outcome. This study aimed to assess the effect of amino acid starvation on doxorubicin-treated breast cancer cells by assessing the roles of autophagy and apoptosis. An in vitro breast cancer model consisting of the normal breast epithelial MCF12A and the metastatic breast cancer MDAMB231 cells was used. Apoptotic and autophagic parameters were assessed following doxorubicin treatments, alone or in combination with bafilomycin, ATG5 siRNA or amino acid starvation. Inhibition of autophagy, through ATG5 siRNA or bafilomycin treatment, increased caspase activity and intracellular doxorubicin concentrations in MCF12A and MDAMB231 cells during doxorubicin treatment. While amino acid starvation increased autophagic activity and decreased caspase activity and intracellular doxorubicin concentrations in MCF12A cells, no changes in autophagic parameters or caspase activity were observed in MDAMB231 cells. Our in vivo data showed that 24 h protein starvation during high dose doxorubicin treatment resulted in increased survival of tumor-bearing GFP-LC3 mice. Results from this study suggest that short term starvation during doxorubicin chemotherapy may be a realistic avenue for adjuvant therapy, especially with regards to the protection of non-cancerous cells. More research is however, needed to fully understand the regulation of autophagic flux during starvation.

Keywords:  amino acids; breast cancer; doxorubicin; nutrient starvation; sensitization

DOI:  https://doi.org/10.3389/fcell.2020.565915
Cell Death Dis. 2020 Nov 11. 11(11): 964

Cancer cell metabolic reprogramming: a keystone for the response to immunotherapy.

Michaël Cerezo, Stéphane Rocchi.

By targeting the tumor microenvironment to stimulate antitumor immunity, immunotherapies have revolutionized cancer treatment. However, many patients do not respond initially or develop secondary resistance. Based on the limited resources in the tumor microenvironment and competition between tumor and immune cells, the field of immune metabolism has produced extensive knowledge showing that targeting metabolism could help to modulate antitumor immunity. However, among all the different potentially targetable metabolic pathways, it remains unclear which have more potential to overcome resistance to immune checkpoint inhibitors. Here, we explore metabolic reprogramming in cancer cells, which might inhibit antitumor immunity, and strategies that can be used to favor the antitumor response.

DOI: https://doi.org/10.1038/s41419-020-03175-5
Eur J Med Chem. 2020 Nov 01. pii: S0223-5234(20)30952-1. [Epub ahead of print] 112980

Discovery and optimization of withangulatin A derivatives as novel glutaminase 1 inhibitors for the treatment of triple-negative breast cancer.

Wu-Xi Zhou, Chen Chen, Xiao-Qin Liu, Ying Li, Yao-Lan Lin, Xiu-Tao Wu, Ling-Yi Kong, Jian-Guang Luo.

  To develop novel GLS1 inhibitors as effective therapeutic agents for triple-negative breast cancer (TNBC), 25 derivatives were synthesized from the natural inhibitor withangulatin A (IC50 = 18.2 μM). Bioassay optimization identified a novel and selective GLS1 inhibitor 7 (IC50 = 1.08 μM). In MDA-MB-231 cells, 7 diminished cellular glutamate levels by blocking glutaminolysis pathway, further triggering the generation of reactive oxygen species to induce caspase-dependent apoptosis. Molecular docking indicated that 7 interacted with a new reacting site of allosteric binding pocket by forming various interactions in GLS1. The intraperitoneal administration of 7 at a dose of 50 mg/kg exhibited remarkable therapeutic effects and no apparent toxicity in the MDA-MB-231 xenograft model, indicating its potential as a novel GLS1 inhibitor for treatment of TNBC.

Keywords:  Antitumor; GLS1 inhibitors; Molecular docking; TNBC; Withangulatin A derivatives

DOI:  https://doi.org/10.1016/j.ejmech.2020.112980
Food Chem. 2020 Nov 01. pii: S0308-8146(20)32373-6. [Epub ahead of print] 128511

Botanical sulfane sulfur donors inhibit ferroptotic cell death caused by the depletion of cysteine.

Seiya Nagai, Masaki Yoshida, Yuta Takigawa, Seiji Torii, Ichiro Koshiishi.

  Inhibitors against cystine-glutamate antiporter, including erastin, elicit ferroptotic cell death. The erastin-induced ferroptotic cell death appears to be caused by cysteine as well as glutathione depletion. Cysteine is an essential substrate for sulfane sulfur producing systems in cells, generating persulfides that function as intracellular antioxidants and intermediates in iron-sulfur cluster production. Therefore, we examined whether botanical sulfane sulfur donors such as diallyl trisulfide (DATS) and dimethyl trisulfide (DMTS) prevent ferroptotic cell death in HT1080 cells treated with erastin. As a result, DMTS (20 μM) and DATS (10 μM) rescued the erastin-treated HT1080 cells by 69.6% and 91.6%, respectively. Furthermore, DMTS-containing squeeze of cabbage (2.0 g/L) and DATS-containing squeeze of garlic (0.07 g/L) rescued the erastin-treated HT1080 cells by 76.5% and almost 100%, respectively. In conclusion, the ingestion of trisulfides may bring about increased resistance to ferroptotic cell death in vivo.

Keywords:  Diallyl trisulfide; Dimethyl trisulfide; Erastin; Ferroptosis; Sulfane sulfur

DOI:  https://doi.org/10.1016/j.foodchem.2020.128511
Front Physiol. 2020 ;11 582258

Crosstalk Between Skeletal Muscle and Immune System: Which Roles Do IL-6 and Glutamine Play?

Patricia S Rogeri, Sandro O Gasparini, Gabriel L Martins, L K F Costa, Caue C Araujo, Rebeca Lugaresi, Mariana Kopfler, Antonio H Lancha.

  The skeletal muscle was always seen from biomechanical and biochemical views. It is well-established that an active muscle brings many benefits for different body organs and tissues, including the immune system. Since the 1970s, many studies have shown the importance of regular exercise and physical activity in increasing the body's ability to fight opportunist infections, as well as a strategy to fight established diseases. This interaction was mainly attributed to the glutamine, a non-essential amino acid produced by the active skeletal muscle and primarily consumed by rapidly dividing cells, including lymphocytes and monocytes/macrophages, as their main source of energy. Therefore, these cells' function would be significantly improved by the presence of a bigger glutamine pool, facilitating phagocytosis, antigen-presentation, proliferative capacity, cytokine synthesis and release, among other functions. Despite its importance, glutamine is not the only molecule to connect these two tissues. The presence of cytokines is crucial for a proper immune system function. Many of them have well-established pro-inflammatory properties, while others are known for their anti-inflammatory role. Interleukin-6 (IL-6), however, has been in the center of many scientific discussions since it can act as pro- and anti-inflammatory cytokine depending on the tissue that releases it. Skeletal muscle is an essential source of IL-6 with anti-inflammatory properties, regulating the function of the immune cells after tissue injury and the healing process. Therefore, this review aims to discuss further the role of these four components (glutamine, and interleukin-6, and its interface with monocytes/macrophages, and lymphocytes) on the communication between the skeletal muscle and the immune system.

Keywords:  glutamine; immune system; interleukin-6; lymphocytes; macrophages; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2020.582258
Bioessays. 2020 Nov 09. e2000160

Can natural selection and druggable targets synergize? Of nutrient scarcity, cancer, and the evolution of cooperation.

Neil W Blackstone, Jordan U Gutterman.

  Since the dawn of molecular biology, cancer therapy has focused on druggable targets. Despite some remarkable successes, cell-level evolution remains a potent antagonist to this approach. We suggest that a deeper understanding of the breakdown of cooperation can synergize the evolutionary and druggable-targets approaches. Complexity requires cooperation, whether between cells of different species (symbiosis) or between cells of the same organism (multicellularity). Both forms of cooperation may be associated with nutrient scarcity, which in turn may be associated with a chemiosmotic metabolism. A variety of examples from modern organisms supports these generalities. Indeed, mammalian cancers-unicellular, glycolytic, and fast-replicating-parallel these examples. Nutrient scarcity, chemiosmosis, and associated signaling may favor cooperation, while under conditions of nutrient abundance a fermentative metabolism may signal the breakdown of cooperation. Manipulating this metabolic milieu may potentiate the effects of targeted therapeutics. Specific opportunities are discussed in this regard, including avicins, a novel plant product.

Keywords:  avicins; chemiosmosis; corals; evolutionary conflict; glycolysis; slime molds; yeast

DOI:  https://doi.org/10.1002/bies.202000160
IUBMB Life. 2020 Nov 12.

Mitochondria and nucleus cross-talk: Signaling in metabolism, apoptosis, and differentiation, and function in cancer.

Anna Shteinfer-Kuzmine, Ankit Verma, Tasleem Arif, Or Aizenberg, Avijit Paul, Varda Shoshan-Barmaz.

  The cross-talk between the mitochondrion and the nucleus regulates cellular functions, including differentiation and adaptation to stress. Mitochondria supply metabolites for epigenetic modifications and other nuclear-associated activities and certain mitochondrial proteins were found in the nucleus. The voltage-dependent anion channel 1 (VDAC1), localized at the outer mitochondrial membrane (OMM) is a central protein in controlling energy production, cell growth, Ca2+ homeostasis, and apoptosis. To alter the cross-talk between the mitochondria and the nucleus, we used specific siRNA to silence the expression of VDAC1 in glioblastoma (GBM) U87-MG and U118-MG cell-derived tumors, and then monitored the nuclear localization of mitochondrial proteins and the methylation and acetylation of histones. Depletion of VDAC1 from tumor cells reduced metabolism, leading to inhibition of tumor growth, and several tumor-associated processes and signaling pathways linked to cancer development. In addition, we demonstrate that certain mitochondrial pro-apoptotic proteins such as caspases 3, 8, and 9, and p53 were unexpectedly overexpressed in tumors, suggesting that they possess additional non-apoptotic functions. VDAC1 depletion and metabolic reprograming altered their expression levels and subcellular localization, specifically their translocation to the nucleus. In addition, VDAC1 depletion also leads to epigenetic modifications of histone acetylation and methylation, suggesting that the interchange between metabolism and cancer signaling pathways involves mitochondria-nucleus cross-talk. The mechanisms regulating mitochondrial protein trafficking into and out of the nucleus and the role these proteins play in the nucleus remain to be elucidated.

Keywords:  VDAC1; apoptosis; cancer; epigenetics; metabolism; mitochondria; nuclear

DOI:  https://doi.org/10.1002/iub.2407
Biochem Biophys Res Commun. 2020 Nov 05. pii: S0006-291X(20)32013-1. [Epub ahead of print]

Sorafenib induces mitochondrial dysfunction and exhibits synergistic effect with cysteine depletion by promoting HCC cells ferroptosis.

Yanchun Li, Jun Xia, Fangchun Shao, Yan Zhou, Jiaqi Yu, Hengyu Wu, Jing Du, Xueying Ren.

  Hepatocellular carcinoma (HCC) is one of the most common malignant cancers worldwide. The prognosis of HCC remains poor. Currently, sorafenib is the first-line drug for advanced HCC. Although sorafenib's mechanism of action involving several established cancer-related protein kinase targets is well-characterized, the underlying molecular mechanism is still unclear. Here, we found that sorafenib inhibited viability, proliferation, and migration of HCC cells in a dose-dependent manner. Sorafenib treatment of HCC cells destroyed mitochondrial morphology, accompanied by decreased activity of oxidative phosphorylation, collapse of mitochondrial membrane potential, and reduced synthesis of ATP, with consequent cell death due to ferroptosis. Pharmacological utilization of glutathione (GSH) rescued the sorafenib-induced ferroptosis, eliminated the accumulation of cellular mitochondrial reactive oxygen species (ROS), and lipid peroxide. GSH depletion through cysteine deprivation or cysteinase inhibition exacerbated sorafenib-induced ferroptotic cell death and lipid peroxides generation, and enhanced oxidative stress and mitochondrial ROS accumulation. Collectively, these findings indicate that depletion of cysteine acts synergistically with sorafenib and renders HCC cells vulnerable to ferroptosis, presenting the potential value of new therapeutic combinations for advanced HCC.

Keywords:  Cysteine; Glutathione; Hepatocellular carcinoma; Mitochondria; Oxidative stress; Sorafenib

DOI:  https://doi.org/10.1016/j.bbrc.2020.10.083
Amino Acids. 2020 Nov 11.

Plasma free amino acid profiling as metabolomic diagnostic and prognostic biomarker in paediatric cancer patients: a follow-up study.

Anna Synakiewicz, Anna Stanislawska-Sachadyn, Malgorzata Sawicka-Zukowska, Grazyna Galezowska, Joanna Ratajczyk, Anna Owczarzak, Malgorzata Skuza, Lidia Wolska, Teresa Stachowicz-Stencel.

  Amino acids (AAs) play a crucial role in cancer cell metabolism. Levels of 22 plasma AAs at the time of diagnosis and after treatment were established among 39 pediatric cancer patients and 33 healthy children. Glutamic acid levels decreased and tryptophan levels increased during treatment. Cancer patients presented significantly lower levels of glutamine and leucine post-treatment while levels of 12 other AAs were higher comparing to controls. Results suggest that plasma free AA profile may serve as a prognostic biomarker.

Keywords:  Amino acid profile; Cancer; Metabolomics; Tumor biomarkers

DOI:  https://doi.org/10.1007/s00726-020-02910-8
Cancer Res. 2020 Nov 10. pii: canres.1488.2020. [Epub ahead of print]

Frizzled-7 Identifies Platinum Tolerant Ovarian Cancer Cells Susceptible to Ferroptosis.

Yinu Wang, Guangyuan Zhao, Salvatore Condello, Hao Huang, Horacio Cardenas, Edward J Tanner, Jianjun Wei, Yanrong Ji, Junjie Li, Yuying Tan, Ramana V Davuluri, Marcus E Peter, Ji-Xin Cheng, Daniela Matei.

Defining traits of platinum-tolerant cancer cells could expose new treatment vulnerabilities. Here, new markers associated with platinum-tolerant cells and tumors were identified using in vitro and in vivo ovarian cancer (OC) models treated repetitively with carboplatin and validated in human specimens. Platinum-tolerant cells and tumors were enriched in ALDH (+) cells, formed more spheroids, and expressed increased levels of stemness-related transcription factors compared to parental cells. Additionally, platinum-tolerant cells and tumors exhibited expression of the Wnt receptor Frizzled 7 (FZD7). Knockdown of FZD7 improved sensitivity to platinum, decreased spheroid formation, and delayed tumor initiation. The molecular signature distinguishing FZD7(+) from FZD7(-) cells included epithelial-to-mesenchymal (EMT), stemness, and oxidative phosphorylation-enriched gene sets. Overexpression of FZD7 activated the oncogenic factor Tp63, driving upregulation of glutathione metabolism pathways, including glutathione peroxidase 4 (GPX4), which protected cells from chemotherapy-induced oxidative stress. FZD7(+) platinum-tolerant OC cells were more sensitive and underwent ferroptosis after treatment with GPX4 inhibitors. FZD7, Tp63, and glutathione metabolism gene sets were strongly correlated in the OC Tumor Cancer Genome Atlas (TCGA) database and in human OC specimens residual after chemotherapy. These results support the existence of a platinum-tolerant cell population with partial stem cell features, characterized by FZD7 expression and dependent on FZD7-β-catenin-Tp63-GPX4 pathway for survival. These findings reveal a novel therapeutic vulnerability of platinum-tolerant cancer cells and provide new insight into a potential "persister cancer cell" phenotype.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-1488
Mol Med Rep. 2020 Dec;22(6): 4981-4991

Role of different immune cells and metabolic pathways in modulating the immune response in pancreatic cancer (Review).

Nnenna Elebo, Pascaline Fru, Jones Omoshoro-Jones, Geoffrey Patrick Candy, Ekene Emmanuel Nweke.

Pancreatic cancer is an aggressive cancer, making it a leading cause of cancer‑related deaths. It is characteristically resistant to treatment, which results in low survival rates. In pancreatic cancer, immune cells undergo transitions that can inhibit or promote their functions, enabling treatment resistance and tumor progression. These transitions can be fostered by metabolic pathways that are dysregulated during tumorigenesis. The present review aimed to summarize the different immune cells and their roles in pancreatic cancer. The review also highlighted the individual metabolic pathways in pancreatic cancer and how they enable transitions in immune cells. Finally, the potential of targeting metabolic pathways for effective therapeutic strategies was considered.

DOI: https://doi.org/10.3892/mmr.2020.11622
Redox Biol. 2020 Nov 03. pii: S2213-2317(20)30985-X. [Epub ahead of print]38 101780

Regulation of PD-L1 expression in K-ras-driven cancers through ROS-mediated FGFR1 signaling.

Christophe Glorieux, Xiaojun Xia, Yong-Qiao He, Yumin Hu, Kelly Cremer, Annie Robert, Junchen Liu, Fen Wang, Jianhua Ling, Paul J Chiao, Peng Huang.

  K-ras mutations are major genetic events that drive cancer development associated with aggressive malignant phenotypes, while expression of the immune checkpoint molecule PD-L1 plays a key role in cancer evasion of the immune surveillance that also profoundly affects the patient outcome. However, the relationship between K-ras oncogenic signal and PD-L1 expressions as an important area that requires further investigation. Using both in vitro and in vivo experimental models of K-ras-driven cancer, we found that oncogenic K-ras significantly enhanced PD-L1 expression through a redox-mediated mechanism. Activation of K-rasG12V promoted ROS generation and induced FGFR1 expression, leading to a significant upregulation of PD-L1. We further showed that exogenous ROS such as hydrogen peroxide alone was sufficient to activate FGFR1 and induce PD-L1, while antioxidants could largely abrogate PD-L1 expression in K-ras mutant cells, indicating a critical role of redox regulation. Importantly, genetic knockout of FGFR1 led to a decrease in PD-L1 expression, and impaired tumor growth in vivo due to a significant increase of T cell infiltration in the tumor tissues and thus enhanced T-cell-mediated tumor suppression. Our study has identified a novel mechanism by which K-ras promotes PD-L1 expression, and suggests that modulation of ROS or inhibition of the FGFR1 pathway could be a novel strategy to abrogate PD-L1-mediated immunosuppression and thus potentially improve the efficacy of immunotherapy in K-ras-driven cancers.

Keywords:  FGFR1; K-ras; PD-L1; ROS

DOI:  https://doi.org/10.1016/j.redox.2020.101780
PLoS Biol. 2020 Nov 13. 18(11): e3000872

Nucleotide de novo synthesis increases breast cancer stemness and metastasis via cGMP-PKG-MAPK signaling pathway.

Yajing Lv, Xiaoshuang Wang, Xiaoyu Li, Guangwei Xu, Yuting Bai, Jiayi Wu, Yongjun Piao, Yi Shi, Rong Xiang, Longlong Wang.

Metabolic reprogramming to fulfill the biosynthetic and bioenergetic demands of cancer cells has aroused great interest in recent years. However, metabolic reprogramming for cancer metastasis has not been well elucidated. Here, we screened a subpopulation of breast cancer cells with highly metastatic capacity to the lung in mice and investigated the metabolic alternations by analyzing the metabolome and the transcriptome, which were confirmed in breast cancer cells, mouse models, and patients' tissues. The effects and the mechanisms of nucleotide de novo synthesis in cancer metastasis were further evaluated in vitro and in vivo. In our study, we report an increased nucleotide de novo synthesis as a key metabolic hallmark in metastatic breast cancer cells and revealed that enforced nucleotide de novo synthesis was enough to drive the metastasis of breast cancer cells. An increased key metabolite of de novo synthesis, guanosine-5'-triphosphate (GTP), is able to generate more cyclic guanosine monophosphate (cGMP) to activate cGMP-dependent protein kinases PKG and downstream MAPK pathway, resulting in the increased tumor cell stemness and metastasis. Blocking de novo synthesis by silencing phosphoribosylpyrophosphate synthetase 2 (PRPS2) can effectively decrease the stemness of breast cancer cells and reduce the lung metastasis. More interestingly, in breast cancer patients, the level of plasma uric acid (UA), a downstream metabolite of purine, is tightly correlated with patient's survival. Our study uncovered that increased de novo synthesis is a metabolic hallmark of metastatic breast cancer cells and its metabolites can regulate the signaling pathway to promote the stemness and metastasis of breast cancer.

DOI: https://doi.org/10.1371/journal.pbio.3000872
Nat Rev Mol Cell Biol. 2020 Nov 13.

Crosstalk between mechanotransduction and metabolism.

Patrizia Romani, Lorea Valcarcel-Jimenez, Christian Frezza, Sirio Dupont.

Mechanical forces shape cells and tissues during development and adult homeostasis. In addition, they also signal to cells via mechanotransduction pathways to control cell proliferation, differentiation and death. These processes require metabolism of nutrients for both energy generation and biosynthesis of macromolecules. However, how cellular mechanics and metabolism are connected is still poorly understood. Here, we discuss recent evidence indicating how the mechanical cues exerted by the extracellular matrix (ECM), cell-ECM and cell-cell adhesion complexes influence metabolic pathways. Moreover, we explore the energy and metabolic requirements associated with cell mechanics and ECM remodelling, implicating a reciprocal crosstalk between cell mechanics and metabolism.

DOI: https://doi.org/10.1038/s41580-020-00306-w
Curr Opin Immunol. 2020 Nov 07. pii: S0952-7915(20)30111-4. [Epub ahead of print]68 72-82

Metabolic regulation of innate immune cell phenotypes during wound repair and regeneration.

Ajoy Aloysius, Sandeep Saxena, Ashley W Seifert.

Metabolism regulates an array of cellular processes from embryonic development through adulthood. These include proliferation, differentiation and the effector functions of adult cells to maintain homeostasis and repair. It is becoming clear that bioenergetic shifts can control how cells respond to environmental disruptions during tissue injury to initiate a healing response. Specifically, innate immune cells shift their phenotypes to initiate and resolve inflammation, and there is intense interest to understand how these responses might regulate healing outcomes. Here, we review recent literature describing how cellular metabolism and metabolic byproducts regulate phenotype conversions among innate immune cells. Although most studies of this kind do not focus on tissue damage, we discuss how metabolic regulation of these phenotypes promotes tissue repair. In particular, we provide a framework for considering the extent to which altering the innate immune response might shift fibrotic repair towards regenerative healing.

DOI: https://doi.org/10.1016/j.coi.2020.10.012
Mol Med Rep. 2020 Dec;22(6): 4967-4980

Molecular mechanisms of cancer cachexia‑induced muscle atrophy (Review).

Wei Yang, Jianhui Huang, Hui Wu, Yuqing Wang, Zhiyin Du, Yuanbo Ling, Weizhuo Wang, Qian Wu, Wenbin Gao.

Muscle atrophy is a severe clinical problem involving the loss of muscle mass and strength that frequently accompanies the development of numerous types of cancer, including pancreatic, lung and gastric cancers. Cancer cachexia is a multifactorial syndrome characterized by a continuous decline in skeletal muscle mass that cannot be reversed by conventional nutritional therapy. The pathophysiological characteristic of cancer cachexia is a negative protein and energy balance caused by a combination of factors, including reduced food intake and metabolic abnormalities. Numerous necessary cellular processes are disrupted by the presence of abnormal metabolites, which mediate several intracellular signaling pathways and result in the net loss of cytoplasm and organelles in atrophic skeletal muscle during various states of cancer cachexia. Currently, the clinical morbidity and mortality rates of patients with cancer cachexia are high. Once a patient enters the cachexia phase, the consequences are difficult to reverse and the treatment methods for cancer cachexia are very limited. The present review aimed to summarize the recent discoveries regarding the pathogenesis of cancer cachexia‑induced muscle atrophy and provided novel ideas for the comprehensive treatment to improve the prognosis of affected patients.

DOI: https://doi.org/10.3892/mmr.2020.11608
Cancers (Basel). 2020 Nov 06. pii: E3292. [Epub ahead of print]12(11):

Cancer Alters the Metabolic Fingerprint of Extracellular Vesicles.

Mari Palviainen, Kirsi Laukkanen, Zeynep Tavukcuoglu, Vidya Velagapudi, Olli Kärkkäinen, Kati Hanhineva, Seppo Auriola, Annamari Ranki, Pia Siljander.

  Cancer alters cell metabolism. How these changes are manifested in the metabolite cargo of cancer-derived extracellular vesicles (EVs) remains poorly understood. To explore these changes, EVs from prostate, cutaneous T-cell lymphoma (CTCL), colon cancer cell lines, and control EVs from their noncancerous counterparts were isolated by differential ultracentrifugation and analyzed by nanoparticle tracking analysis (NTA), electron microscopy (EM), Western blotting, and liquid chromatography-mass spectrometry (LC-MS). Although minor differences between the cancerous and non-cancerous cell-derived EVs were observed by NTA and Western blotting, the largest differences were detected in their metabolite cargo. Compared to EVs from noncancerous cells, cancer EVs contained elevated levels of soluble metabolites, e.g., amino acids and B vitamins. Two metabolites, proline and succinate, were elevated in the EV samples of all three cancer types. In addition, folate and creatinine were elevated in the EVs from prostate and CTCL cancer cell lines. In conclusion, we present the first evidence in vitro that the altered metabolism of different cancer cells is reflected in common metabolite changes in their EVs. These results warrant further studies on the significance and usability of this metabolic fingerprint in cancer.

Keywords:  cancer metabolism; colon cancer; cutaneous T-cell lymphoma; extracellular vesicles; prostate cancer

DOI:  https://doi.org/10.3390/cancers12113292