bims-glucam 2020-12-06 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2020–12–06
25 papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine metabolism in osteoprogenitors is required for bone mass accrual and PTH-induced bone anabolism in male mice.
Kinetic Modeling of 18F-(2S,4R)4-Fluoroglutamine in Mouse Models of Breast Cancer to Estimate Glutamine Pool Size as an Indicator of Tumor Glutamine Metabolism.
Biphasic regulation of glutamine consumption by WNT during osteoblast differentiation.
Microfluidic Tumor-on-a-Chip Model to Study Tumor Metabolic Vulnerability.
SIRT3, a metabolic target linked to ataxia-telangiectasia mutated (ATM) gene deficiency in diffuse large B-cell lymphoma.
On the Origin of ATP Synthesis in Cancer.
Metabolomics revealed the influence of breast cancer on lymphatic endothelial cell metabolism, metabolic crosstalk, and lymphangiogenic signaling in co-culture.
Metabolic traits ruling the specificity of the immune response in different cancer types.
Post-Translational Modification Analysis of VDAC1 in ALS-SOD1 Model Cells Reveals Specific Asparagine and Glutamine Deamidation.
Revisiting prostate cancer metabolism: From metabolites to disease and therapy.
Amino acid transporter LAT1 in tumor-associated vascular endothelium promotes angiogenesis by regulating cell proliferation and VEGF-A-dependent mTORC1 activation.
Isocitrate Dehydrogenase 2 Inhibitors for the treatment of Hematologic Malignancies: Advances and Future Opportunities.
Serine and Metabolism Regulation: A Novel Mechanism in Antitumor Immunity and Senescence.
Circular RNA circGSK3B Promotes Cell Proliferation, Migration, and Invasion by Sponging miR-1265 and Regulating CAB39 Expression in Hepatocellular Carcinoma.
mTORC1-mediated amino acid signaling is critical for cell fate determination under transplant-induced stress.
FBW7-NRA41-SCD1 axis synchronously regulates apoptosis and ferroptosis in pancreatic cancer cells.
Mutation-selection balance and compensatory mechanisms in tumour evolution.
Cancer Stem Cell-Associated Pathways in the Metabolic Reprogramming of Breast Cancer.
Beyond energy storage: roles of glycogen metabolism in health and disease.
Iron Dysregulation in Human Cancer: Altered Metabolism, Biomarkers for Diagnosis, Prognosis, Monitoring and Rationale for Therapy.
Stresses in the metastatic cascade: molecular mechanisms and therapeutic opportunities.
NRF2 and the Ambiguous Consequences of Its Activation during Initiation and the Subsequent Stages of Tumourigenesis.
Ferroptosis: molecular mechanisms and health implications.
The Center Cannot Hold: NRF2 Battles Ferroptosis in the 3rd Dimension.
Metabolic Drug Response Phenotyping in Colorectal Cancer Organoids by LC-QTOF-MS.

J Bone Miner Res. 2020 Nov 30.

Glutamine metabolism in osteoprogenitors is required for bone mass accrual and PTH-induced bone anabolism in male mice.

Steve Stegen, Claire-Sophie Devignes, Sophie Torrekens, Riet Van Looveren, Peter Carmeliet, Geert Carmeliet.

  Skeletal homeostasis critically depends on the proper anabolic functioning of osteolineage cells. Proliferation and matrix synthesis are highly demanding in terms of biosynthesis and bioenergetics, but the nutritional requirements that support these processes in bone-forming cells are not fully understood. Here, we show that glutamine metabolism is a major determinant of osteoprogenitor function during bone mass accrual. Genetic inactivation of the rate-limiting enzyme glutaminase 1 (GLS1) results in decreased postnatal bone mass, caused by impaired biosynthesis and cell survival. Mechanistically, we uncovered that GLS1-mediated glutamine catabolism supports nucleotide and amino acid synthesis, required for proliferation and matrix production. In addition, glutamine-derived glutathione prevents accumulation of reactive oxygen species and thereby safeguards cell viability. The pro-anabolic role of glutamine metabolism was further underscored in a model of parathyroid hormone (PTH)-induced bone formation. PTH administration increases glutamine uptake and catabolism, and GLS1 deletion fully blunts the PTH-induced osteoanabolic response. Taken together, our findings indicate that glutamine metabolism in osteoprogenitors is indispensable for bone formation. This article is protected by copyright. All rights reserved.

Keywords:  PTH; biosynthesis; glutamine metabolism; osteoprogenitor; redox homeostasis

DOI:  https://doi.org/10.1002/jbmr.4219
J Nucl Med. 2020 Dec 04. pii: jnumed.120.250977. [Epub ahead of print]

Kinetic Modeling of 18F-(2S,4R)4-Fluoroglutamine in Mouse Models of Breast Cancer to Estimate Glutamine Pool Size as an Indicator of Tumor Glutamine Metabolism.

Varsha Viswanath, Rong Zhou, Hsiaoju Lee, Shihong Li, Abigail Cragin, Robert K Doot, David A Mankoff, Austin R Pantel.

  The PET radiotracer [18F]-(2S,4R)4¬-Fluoroglutamine (18F-Gln) reflects glutamine transport and can be used to infer glutamine metabolism. Mouse xenograft studies have demonstrated that 18F-Gln uptake correlates directly with glutamine pool size and is inversely related to glutamine metabolism through the glutaminase enzyme. To provide a framework for the analysis of 18F-Gln-PET, we have examined 18F-Gln uptake kinetics in mouse models of breast cancer at baseline and after inhibition of glutaminase. We describe results of the pre-clinical analysis and computer simulations with the goal of model validation and performance assessment in anticipation of human breast cancer patient studies. Methods: TNBC and receptor-positive xenografts were implanted in athymic mice. PET mouse imaging was performed at baseline and after treatment with a glutaminase inhibitor (CB-839, Calithera, Inc.) or a vehicle solution for a total of four mouse groups. Dynamic PET images were obtained for one hour beginning at the time of intravenous injection of 18F-FGln. Kinetic analysis and computer simulations were performed on a representative time-activity curves (TAC), testing 1- and 2-compartment models to describe kinetics. Results: Dynamic imaging for one hour captured blood and tumor TACs indicative of largely reversible uptake of 18F-FGln in tumors. Consistent with this observation, a two-compartment model indicated a relatively low estimate of trapping (k3), suggesting that the one-compartment model is preferable. Logan plot graphical analysis demonstrated late linearity, supporting reversible kinetics and modeling with a single compartment. Analysis of the mouse data and simulations suggests that estimates of glutamine pools size, specifically the VD for 18F-FGln, were more reliably estimated using the one-compartment reversible model compared to the two-compartment irreversible model. Tumor-to-blood ratios, a more practical potential proxy of VD, demonstrated good correlation with volume of distribution from single-compartment models and Logan analyses. Conclusion: Kinetic analysis of dynamic 18F-Gln-PET images demonstrated the ability to measure VD to estimate glutamine pool size, a key indicator of cellular glutamine metabolism, by both a one-compartment model and Logan analysis. Changes in VD with glutaminase inhibition supports the ability to assess response to glutamine metabolism-targeted therapy. Concordance of kinetic measures with tumor-to-blood ratios provides a clinically feasible approach for human imaging.

Keywords:  18F-Glutamine; Animal imaging; Kinetic modeling; Numerical simulations; Oncology: Breast; PET; Radiotracer Tissue Kinetics; Triple negative breast cancer

DOI:  https://doi.org/10.2967/jnumed.120.250977
J Cell Sci. 2020 Dec 01. pii: jcs.251645. [Epub ahead of print]

Biphasic regulation of glutamine consumption by WNT during osteoblast differentiation.

Leyao Shen, Deepika Sharma, Yilin Yu, Fanxin Long, Courtney Karner.

  Osteoblasts are the principal bone forming cells. As such, osteoblasts have enhanced demand for amino acids to sustain high rates of matrix synthesis associated with bone formation. The precise systems utilized by osteoblasts to meet these synthetic demands are not well understood. WNT signaling is known to rapidly stimulate glutamine uptake during osteoblast differentiation. Using a cell biology approach, we identified two amino acid transporters, Slc7a7 and Slc1a5, as the primary transporters of glutamine in response to WNT. Slc1a5 mediates the majority of glutamine uptake, whereas Slc7a7 mediates the rapid increase in glutamine uptake in response to WNT. Mechanistically, WNT signals through the canonical/β-catenin dependent pathway to rapidly induce Slc7a7 expression. Conversely, Slc1a5 expression is regulated by the transcription factor ATF4 downstream of the mTORC1 pathway. Targeting either Slc1a5 or Slc7a7 using shRNA reduced WNT induced glutamine uptake and prevented osteoblast differentiation. Collectively these data highlight the critical nature of glutamine transport for WNT induced osteoblast differentiation.

Keywords:  Glutamine; Osteoblast; Slc1a5; Slc7a7; WNT; β-catenin

DOI:  https://doi.org/10.1242/jcs.251645
Int J Mol Sci. 2020 Nov 28. pii: E9075. [Epub ahead of print]21(23):

Microfluidic Tumor-on-a-Chip Model to Study Tumor Metabolic Vulnerability.

Jose M Ayuso, Shujah Rehman, Mehtab Farooqui, María Virumbrales-Muñoz, Vijayasaradhi Setaluri, Melissa C Skala, David J Beebe.

  Tumor-specific metabolic adaptations offer an interesting therapeutic opportunity to selectively destroy cancer cells. However, solid tumors also present gradients of nutrients and waste products across the tumor mass, forcing tumor cells to adapt their metabolism depending on nutrient availability in the surrounding microenvironment. Thus, solid tumors display a heterogenous metabolic phenotype across the tumor mass, which complicates the design of effective therapies that target all the tumor populations present. In this work, we used a microfluidic device to study tumor metabolic vulnerability to several metabolic inhibitors. The microdevice included a central chamber to culture tumor cells in a three-dimensional (3D) matrix, and a lumen in one of the chamber flanks. This design created an asymmetric nutrient distribution across the central chamber, generating gradients of cell viability. The results revealed that tumor cells located in a nutrient-enriched environment showed low to no sensitivity to metabolic inhibitors targeting glycolysis, fatty acid oxidation, or oxidative phosphorylation. Conversely, when cell density inside of the model was increased, compromising nutrient supply, the addition of these metabolic inhibitors disrupted cellular redox balance and led to tumor cell death.

Keywords:  microfluidics; redox ratio; tumor metabolism; tumor-on-a-chip

DOI:  https://doi.org/10.3390/ijms21239075
Sci Rep. 2020 Dec 03. 10(1): 21159

SIRT3, a metabolic target linked to ataxia-telangiectasia mutated (ATM) gene deficiency in diffuse large B-cell lymphoma.

Kavita Bhalla, Sausan Jaber, Kayla Reagan, Arielle Hamburg, Karen F Underwood, Aditya Jhajharia, Maninder Singh, Binny Bhandary, Shambhu Bhat, Nahid M Nanaji, Ruching Hisa, Carrie McCracken, Heather Huot Creasy, Rena G Lapidus, Tami Kingsbury, Dirk Mayer, Brian Polster, Ronald B Gartenhaus.

Inactivation of Ataxia-telangiectasia mutated (ATM) gene results in an increased risk to develop cancer. We show that ATM deficiency in diffuse large B-cell lymphoma (DLBCL) significantly induce mitochondrial deacetylase sirtuin-3 (SIRT3) activity, disrupted mitochondrial structure, decreased mitochondrial respiration, and compromised TCA flux compared with DLBCL cells expressing wild type (WT)-ATM. This corresponded to enrichment of glutamate receptor and glutamine pathways in ATM deficient background compared to WT-ATM DLBCL cells. ATM-/- DLBCL cells have decreased apoptosis in contrast to radiosensitive non-cancerous A-T cells. In vivo studies using gain and loss of SIRT3 expression showed that SIRT3 promotes growth of ATM CRISPR knockout DLBCL xenografts compared to wild-type ATM control xenografts. Importantly, screening of DLBCL patient samples identified SIRT3 as a putative therapeutic target, and validated an inverse relationship between ATM and SIRT3 expression. Our data predicts SIRT3 as an important therapeutic target for DLBCL patients with ATM null phenotype.

DOI: https://doi.org/10.1038/s41598-020-78193-6
iScience. 2020 Nov 20. 23(11): 101761

On the Origin of ATP Synthesis in Cancer.

Thomas N Seyfried, Gabriel Arismendi-Morillo, Purna Mukherjee, Christos Chinopoulos.

  ATP is required for mammalian cells to remain viable and to perform genetically programmed functions. Maintenance of the ΔG'ATP hydrolysis of -56 kJ/mole is the endpoint of both genetic and metabolic processes required for life. Various anomalies in mitochondrial structure and function prevent maximal ATP synthesis through OxPhos in cancer cells. Little ATP synthesis would occur through glycolysis in cancer cells that express the dimeric form of pyruvate kinase M2. Mitochondrial substrate level phosphorylation (mSLP) in the glutamine-driven glutaminolysis pathway, substantiated by the succinate-CoA ligase reaction in the TCA cycle, can partially compensate for reduced ATP synthesis through both OxPhos and glycolysis. A protracted insufficiency of OxPhos coupled with elevated glycolysis and an auxiliary, fully operational mSLP, would cause a cell to enter its default state of unbridled proliferation with consequent dedifferentiation and apoptotic resistance, i.e., cancer. The simultaneous restriction of glucose and glutamine offers a therapeutic strategy for managing cancer.

Keywords:  Biochemistry; Biological Sciences; Cancer Systems Biology; Cell Biology

DOI:  https://doi.org/10.1016/j.isci.2020.101761
Sci Rep. 2020 Dec 04. 10(1): 21244

Metabolomics revealed the influence of breast cancer on lymphatic endothelial cell metabolism, metabolic crosstalk, and lymphangiogenic signaling in co-culture.

Suehelay Acevedo-Acevedo, Douglas C Millar, Aaron D Simmons, Peter Favreau, Paulo F Cobra, Melissa Skala, Sean P Palecek.

Breast cancer metastasis occurs via blood and lymphatic vessels. Breast cancer cells 'educate' lymphatic endothelial cells (LECs) to support tumor vascularization and growth. However, despite known metabolic alterations in breast cancer, it remains unclear how lymphatic endothelial cell metabolism is altered in the tumor microenvironment and its effect in lymphangiogenic signaling in LECs. We analyzed metabolites inside LECs in co-culture with MCF-7, MDA-MB-231, and SK-BR-3 breast cancer cell lines using [Formula: see text] nuclear magnetic resonance (NMR) metabolomics, Seahorse, and the spatial distribution of metabolic co-enzymes using optical redox ratio imaging to describe breast cancer-LEC metabolic crosstalk. LECs co-cultured with breast cancer cells exhibited cell-line dependent altered metabolic profiles, including significant changes in lactate concentration in breast cancer co-culture. Cell metabolic phenotype analysis using Seahorse showed LECs in co-culture exhibited reduced mitochondrial respiration, increased reliance on glycolysis and reduced metabolic flexibility. Optical redox ratio measurements revealed reduced NAD(P)H levels in LECs potentially due to increased NAD(P)H utilization to maintain redox homeostasis. [Formula: see text]-labeled glucose experiments did not reveal lactate shuttling into LECs from breast cancer cells, yet showed other [Formula: see text] signals in LECs suggesting internalized metabolites and metabolic exchange between the two cell types. We also determined that breast cancer co-culture stimulated lymphangiogenic signaling in LECs, yet activation was not stimulated by lactate alone. Increased lymphangiogenic signaling suggests paracrine signaling between LECs and breast cancer cells which could have a pro-metastatic role.

DOI: https://doi.org/10.1038/s41598-020-76394-7
Curr Opin Biotechnol. 2020 Nov 25. pii: S0958-1669(20)30160-9. [Epub ahead of print]68 124-143

Metabolic traits ruling the specificity of the immune response in different cancer types.

Nina C Flerin, Federica Cappellesso, Samantha Pretto, Massimiliano Mazzone.

Cancer immunotherapy aims to augment the response of the patient's own immune system against cancer cells. Despite effective for some patients and some cancer types, the therapeutic efficacy of this treatment is limited by the composition of the tumor microenvironment (TME), which is not well-suited for the fitness of anti-tumoral immune cells. However, the TME differs between cancer types and tissues, thus complicating the possibility of the development of therapies that would be effective in a large range of patients. A possible scenario is that each type of cancer cell, granted by its own mutations and reminiscent of the functions of the tissue of origin, has a specific metabolism that will impinge on the metabolic composition of the TME, which in turn specifically affects T cell fitness. Therefore, targeting cancer or T cell metabolism could increase the efficacy and specificity of existing immunotherapies, improving disease outcome and minimizing adverse reactions.

DOI: https://doi.org/10.1016/j.copbio.2020.10.011
Antioxidants (Basel). 2020 Dec 02. pii: E1218. [Epub ahead of print]9(12):

Post-Translational Modification Analysis of VDAC1 in ALS-SOD1 Model Cells Reveals Specific Asparagine and Glutamine Deamidation.

Maria Gaetana Giovanna Pittalà, Simona Reina, Salvatore Antonio Maria Cubisino, Annamaria Cucina, Beatrice Formicola, Vincenzo Cunsolo, Salvatore Foti, Rosaria Saletti, Angela Messina.

  Mitochondria from affected tissues of amyotrophic lateral sclerosis (ALS) patients show morphological and biochemical abnormalities. Mitochondrial dysfunction causes oxidative damage and the accumulation of ROS, and represents one of the major triggers of selective death of motor neurons in ALS. We aimed to assess whether oxidative stress in ALS induces post-translational modifications (PTMs) in VDAC1, the main protein of the outer mitochondrial membrane and known to interact with SOD1 mutants related to ALS. In this work, specific PTMs of the VDAC1 protein purified by hydroxyapatite from mitochondria of a NSC34 cell line expressing human SOD1G93A, a suitable ALS motor neuron model, were analyzed by tryptic and chymotryptic proteolysis and UHPLC/High-Resolution ESI-MS/MS. We found selective deamidations of asparagine and glutamine of VDAC1 in ALS-related NSC34-SOD1G93A cells but not in NSC34-SOD1WT or NSC34 cells. In addition, we identified differences in the over-oxidation of methionine and cysteines between VDAC1 purified from ALS model or non-ALS NSC34 cells. The specific range of PTMs identified exclusively in VDAC1 from NSC34-SOD1G93A cells but not from NSC34 control lines, suggests the appearance of important changes to the structure of the VDAC1 channel and therefore to the bioenergetics metabolism of ALS motor neurons. Data are available via ProteomeXchange with identifier <PXD022598>.

Keywords:  Orbitrap fusion tribrid; ROS; SOD1; amyotrophic lateral sclerosis; deamidation; mass spectrometry analysis; mitochondria; neurodegeneration; post-translational modifications; voltage dependent anion channel

DOI:  https://doi.org/10.3390/antiox9121218
Med Res Rev. 2020 Dec 04.

Revisiting prostate cancer metabolism: From metabolites to disease and therapy.

Henrique J Cardoso, Tiago M A Carvalho, Lara R S Fonseca, Marília I Figueira, Cátia V Vaz, Sílvia Socorro.

  Prostate cancer (PCa), one of the most commonly diagnosed cancers worldwide, still presents important unmet clinical needs concerning treatment. In the last years, the metabolic reprogramming and the specificities of tumor cells emerged as an exciting field for cancer therapy. The unique features of PCa cells metabolism, and the activation of specific metabolic pathways, propelled the use of metabolic inhibitors for treatment. The present work revises the knowledge of PCa metabolism and the metabolic alterations that underlie the development and progression of the disease. A focus is given to the role of bioenergetic sources, namely, glucose, lipids, and glutamine sustaining PCa cell survival and growth. Moreover, it is described as the action of oncogenes/tumor suppressors and sex steroid hormones in the metabolic reprogramming of PCa. Finally, the status of PCa treatment based on the inhibition of metabolic pathways is presented. Globally, this review updates the landscape of PCa metabolism, highlighting the critical metabolic alterations that could have a clinical and therapeutic interest.

Keywords:  metabolism; prostate cancer; therapy

DOI:  https://doi.org/10.1002/med.21766
J Exp Clin Cancer Res. 2020 Nov 30. 39(1): 266

Amino acid transporter LAT1 in tumor-associated vascular endothelium promotes angiogenesis by regulating cell proliferation and VEGF-A-dependent mTORC1 activation.

Lili Quan, Ryuichi Ohgaki, Saori Hara, Suguru Okuda, Ling Wei, Hiroki Okanishi, Shushi Nagamori, Hitoshi Endou, Yoshikatsu Kanai.

   BACKGROUND: Tumor angiogenesis is regarded as a rational anti-cancer target. The efficacy and indications of anti-angiogenic therapies in clinical practice, however, are relatively limited. Therefore, there still exists a demand for revealing the distinct characteristics of tumor endothelium that is crucial for the pathological angiogenesis. L-type amino acid transporter 1 (LAT1) is well known to be highly and broadly upregulated in tumor cells to support their growth and proliferation. In this study, we aimed to establish the upregulation of LAT1 as a novel general characteristic of tumor-associated endothelial cells as well, and to explore the functional relevance in tumor angiogenesis.
METHODS: Expression of LAT1 in tumor-associated endothelial cells was immunohistologically investigated in human pancreatic ductal adenocarcinoma (PDA) and xenograft- and syngeneic mouse tumor models. The effects of pharmacological and genetic ablation of endothelial LAT1 were examined in aortic ring assay, Matrigel plug assay, and mouse tumor models. The effects of LAT1 inhibitors and gene knockdown on cell proliferation, regulation of translation, as well as on the VEGF-A-dependent angiogenic processes and intracellular signaling were investigated in in vitro by using human umbilical vein endothelial cells.
RESULTS: LAT1 was highly expressed in vascular endothelial cells of human PDA but not in normal pancreas. Similarly, high endothelial LAT1 expression was observed in mouse tumor models. The angiogenesis in ex/in vivo assays was suppressed by abrogating the function or expression of LAT1. Tumor growth in mice was significantly impaired through the inhibition of angiogenesis by targeting endothelial LAT1. LAT1-mediated amino acid transport was fundamental to support endothelial cell proliferation and translation initiation in vitro. Furthermore, LAT1 was required for the VEGF-A-dependent migration, invasion, tube formation, and activation of mTORC1, suggesting a novel cross-talk between pro-angiogenic signaling and nutrient-sensing in endothelial cells.
CONCLUSIONS: These results demonstrate that the endothelial LAT1 is a novel key player in tumor angiogenesis, which regulates proliferation, translation, and pro-angiogenic VEGF-A signaling. This study furthermore indicates a new insight into the dual functioning of LAT1 in tumor progression both in tumor cells and stromal endothelium. Therapeutic inhibition of LAT1 may offer an ideal option to potentiate anti-angiogenic therapies.

Keywords:  Amino acid transporter; Endothelial cell; Tumor angiogenesis; VEGF-A; mTORC1

DOI:  https://doi.org/10.1186/s13046-020-01762-0
Mini Rev Med Chem. 2020 Nov 29.

Isocitrate Dehydrogenase 2 Inhibitors for the treatment of Hematologic Malignancies: Advances and Future Opportunities.

Feng Huang, Tian Tian, Yizhe Wu, Jinxin Che, Haiyan Yang, Xiaowu Dong.

  Tumor cells frequently reprogram cellular metabolism from oxidative phosphorylation to glycolysis. Isocitrate dehydrogenase 2 (IDH2) has been intensely studied due to its involvement in the metabolic activity of cancer cells. Mutations in IDH2 promote neomorphic activity through the generation of oncometabolite 2-hydroxyglutarate (2-HG). The overproduced 2-HG can competitively inhibit α-KG-dependent dioxygenases to trigger cell differentiation disorders, a major cause of blood tumors. This review outlines recent progress in the identification of IDH2 inhibitors in blood cancer to provide reference for ongoing and future clinical studies.

Keywords:  Blood Cancer. ; IDH2; Mutant; Inhibitors; Isocitrate Dehydrogenase 2; Structure-activity relationship

DOI:  https://doi.org/10.2174/1389557520666201130102724
Aging Dis. 2020 Dec;11(6): 1640-1653

Serine and Metabolism Regulation: A Novel Mechanism in Antitumor Immunity and Senescence.

Qi Wu, Xinyue Chen, Juanjuan Li, Shengrong Sun.

  As one of the nonessential amino acids (NEAAs), serine is involved in the anabolism of multiple macromolecular substances by participating in one-carbon unit metabolism. Thus, rapidly proliferating cells such as tumor cells and activated immune cells are highly dependent on serine. Serine supports the proliferation of various immune cells through multiple pathways to enhance the antitumor immune response. Moreover, serine influences aging specificity in an epigenetic and metabolic manner. In this review, we focus on recent advances in the relationship between serine metabolism, antitumor immunity, and senescence. The metabolic regulation of serine seems to be a key point of intervention in antitumor immunity and aging-related disease, providing an opportunity for several novel therapeutics.

Keywords:  Serine; antitumor immunity and senescence; metabolism

DOI:  https://doi.org/10.14336/AD.2020.0314
Front Oncol. 2020 ;10 598256

Circular RNA circGSK3B Promotes Cell Proliferation, Migration, and Invasion by Sponging miR-1265 and Regulating CAB39 Expression in Hepatocellular Carcinoma.

Kai Li, Jiacheng Cao, Zitong Zhang, Keyan Chen, Tieliang Ma, Wenjie Yang, Shikun Yang, Jianhua Rao, Kai Zhang.

  Circular RNAs (circRNAs) have important regulatory roles in the development of various cancers. However, the biological functions and potential molecular mechanisms of circRNAs in hepatocellular carcinoma (HCC) are still unclear. In this study, we investigated the role of a new circRNA-circGSK3B (hsa_circ_0003763) and its molecular mechanism in HCC. We found that circGSK3B was highly expressed in HCC tissues and HCC cell lines. Additionally, the expression level of circGSK3B significantly correlated with HCC tumor size and vascular invasion. Functionally, we confirmed that circGSK3B can promote the proliferation, migration, and invasion of HCC cells in vivo and in vitro. In terms of mechanism, we demonstrated that circGSK3B acts as a miR-1265 sponge, positively regulates the target gene CAB39, and promotes the reprogramming of glutamine metabolism, thereby promoting the progression of HCC. Finally, the classic RNA binding protein QKI was observed to participate in the biogenesis of circGSK3B. In summary, we proved that the circGSK3B-miR-1265-CAB39 axis can promote the proliferation, migration, invasion of HCC cells, indicating that circGSKB may serve as a promising diagnostic and prognostic marker in HCC.

Keywords:  CAB39; QKI; circGSK3B; glutaminolysis; hepatocellular carcinoma; miR-1265

DOI:  https://doi.org/10.3389/fonc.2020.598256
FEBS Lett. 2020 Nov 29.

mTORC1-mediated amino acid signaling is critical for cell fate determination under transplant-induced stress.

Xiaoyan Cheng, Maolin Ge, Shouhai Zhu, Dan Li, Ruiheng Wang, Qiongyu Xu, Zhihong Chen, Shufeng Xie, Han Liu.

  Transplantation of in vitro-manipulated cells is widely used in hematology. While transplantation is well recognized to impose severe stress on transplanted cells, the nature of transplant-induced stress remains elusive. Here we propose that the lack of amino acids in serum is the major cause of transplant-induced stress. Mechanistically, amino acid deficiency decreases protein synthesis and nutrient consummation. However, in cells with overactive AKT and ERK, mTORC1 is not inhibited and protein synthesis remains relatively high. This impaired signaling causes nutrient depletion, cell cycle block, and eventually autophagy and cell death, which can be inhibited by cycloheximide or mTORC1 inhibitors. Thus, mTORC1-mediated amino acid signaling is critical in cell fate determination under transplant-induced stress, and protein synthesis inhibition can improve transplantation efficiency.

Keywords:  amino acid; leukemia; mTORC1; metabolism; transplant-induced stress

DOI:  https://doi.org/10.1002/1873-3468.14008
Redox Biol. 2020 Nov 24. pii: S2213-2317(20)31012-0. [Epub ahead of print]38 101807

FBW7-NRA41-SCD1 axis synchronously regulates apoptosis and ferroptosis in pancreatic cancer cells.

Zeng Ye, Qifeng Zhuo, Qiangsheng Hu, Xiaowu Xu, Mengqi Liu, Zheng Zhang, Wenyan Xu, Wensheng Liu, Guixiong Fan, Yi Qin, Xianjun Yu, Shunrong Ji.

  FBW7 functions as a tumor suppressor by targeting oncoproteins for degradation. Our previous study found FBW7 was low expressed in pancreatic cancer due to sustained activation of Ras-Raf-MEK-ERK pathway, which destabilized FBW7 by phosphorylating at Thr205. MicroPET/CT imaging results revealed that FBW7 substantially decreased 18F-fluorodeoxyglucose uptake in xenograft tumors. Mechanistically, FBW7 inhibited glucose metabolism via c-Myc/TXNIP axis. But in these studies, we observed FBW7 down-regulated genes were widely involved in redox reaction and lipid metabolism. Here we reanalyzed previous gene expression profiling and conducted targeted cell metabolites analysis. Results revealed that FBW7 regulated lipid peroxidation and promoted ferroptosis, a non-apoptotic form of cell death. Mechanistically, we found FBW7 inhibited the expression of stearoyl-CoA desaturase (SCD1) via inhibiting nuclear receptor subfamily 4 group A member 1 (NR4A1). SCD1 was reported to inhibit both ferroptosis and apoptosis, which was consistent with the function of FBW7 and NR4A1, another FBW7 down-regulated gene in the gene expression profiling. Moreover, FBW7 potentiated cytotoxic effect of gemcitabine via activating ferroptosis and apoptosis. Combination ferroptosis inducers and apoptosis activators could also significantly potentiated cytotoxic effect of gemcitabine in pancreatic cancer. Therefore, our findings might provide new strategies for the comprehensive treatment of pancreatic cancer.

Keywords:  Apoptosis; FBW7; Ferroptosis; Pancreatic cancer

DOI:  https://doi.org/10.1016/j.redox.2020.101807
Nat Rev Genet. 2020 Nov 30.

Mutation-selection balance and compensatory mechanisms in tumour evolution.

Erez Persi, Yuri I Wolf, David Horn, Eytan Ruppin, Francesca Demichelis, Robert A Gatenby, Robert J Gillies, Eugene V Koonin.

Intratumour heterogeneity and phenotypic plasticity, sustained by a range of somatic aberrations, as well as epigenetic and metabolic adaptations, are the principal mechanisms that enable cancers to resist treatment and survive under environmental stress. A comprehensive picture of the interplay between different somatic aberrations, from point mutations to whole-genome duplications, in tumour initiation and progression is lacking. We posit that different genomic aberrations generally exhibit a temporal order, shaped by a balance between the levels of mutations and selective pressures. Repeat instability emerges first, followed by larger aberrations, with compensatory effects leading to robust tumour fitness maintained throughout the tumour progression. A better understanding of the interplay between genetic aberrations, the microenvironment, and epigenetic and metabolic cellular states is essential for early detection and prevention of cancer as well as development of efficient therapeutic strategies.

DOI: https://doi.org/10.1038/s41576-020-00299-4
Int J Mol Sci. 2020 Nov 30. pii: E9125. [Epub ahead of print]21(23):

Cancer Stem Cell-Associated Pathways in the Metabolic Reprogramming of Breast Cancer.

Sara El-Sahli, Lisheng Wang.

  Metabolic reprogramming of cancer is now considered a hallmark of many malignant tumors, including breast cancer, which remains the most commonly diagnosed cancer in women all over the world. One of the main challenges for the effective treatment of breast cancer emanates from the existence of a subpopulation of tumor-initiating cells, known as cancer stem cells (CSCs). Over the years, several pathways involved in the regulation of CSCs have been identified and characterized. Recent research has also shown that CSCs are capable of adopting a metabolic flexibility to survive under various stressors, contributing to chemo-resistance, metastasis, and disease relapse. This review summarizes the links between the metabolic adaptations of breast cancer cells and CSC-associated pathways. Identification of the drivers capable of the metabolic rewiring in breast cancer cells and CSCs and the signaling pathways contributing to metabolic flexibility may lead to the development of effective therapeutic strategies. This review also covers the role of these metabolic adaptation in conferring drug resistance and metastasis in breast CSCs.

Keywords:  breast cancer; cancer stem cells; metabolism; signaling pathways

DOI:  https://doi.org/10.3390/ijms21239125
FEBS J. 2020 Nov 29.

Beyond energy storage: roles of glycogen metabolism in health and disease.

Huafeng Zhang, Jingwei Ma, Ke Tang, Bo Huang.

  Beyond storing and supplying energy in the liver and muscles, glycogen also plays critical roles in cell differentiation, signaling, redox regulation and stemness under various physiological and pathophysiological conditions. Such versatile functions have been revealed by various forms of glycogen storage diseases. Here, we outline the source of carbon flux in glycogen metabolism and discuss how glycogen metabolism guides CD8+ T cell memory formation and maintenance. Likewise, we review how this affects macrophage polarization and inflammatory responses. Furthermore, we dissect how glycogen metabolism supports tumor development by promoting tumor-repopulating cell growth in hypoxic tumor microenvironments. This review highlights the essential role of the gluconeogenesis-glycogenesis-glycogenolysis-PPP metabolic chain in redox homeostasis, thus providing insights into potential therapeutic strategies against major chronic diseases including cancer.

Keywords:  G6P; Glycogen metabolism; PPP; UDPG; gluconeogenesis

DOI:  https://doi.org/10.1111/febs.15648
Cancers (Basel). 2020 Nov 26. pii: E3524. [Epub ahead of print]12(12):

Iron Dysregulation in Human Cancer: Altered Metabolism, Biomarkers for Diagnosis, Prognosis, Monitoring and Rationale for Therapy.

Pierre Lelièvre, Lucie Sancey, Jean-Luc Coll, Aurélien Deniaud, Benoit Busser.

  Iron (Fe) is a trace element that plays essential roles in various biological processes such as DNA synthesis and repair, as well as cellular energy production and oxygen transport, and it is currently widely recognized that iron homeostasis is dysregulated in many cancers. Indeed, several iron homeostasis proteins may be responsible for malignant tumor initiation, proliferation, and for the metastatic spread of tumors. A large number of studies demonstrated the potential clinical value of utilizing these deregulated proteins as prognostic and/or predictive biomarkers of malignancy and/or response to anticancer treatments. Additionally, the iron present in cancer cells and the importance of iron in ferroptosis cell death signaling pathways prompted the development of therapeutic strategies against advanced stage or resistant cancers. In this review, we select relevant and promising studies in the field of iron metabolism in cancer research and clinical oncology. Besides this, we discuss some co-existing discrepant findings. We also present and discuss the latest lines of research related to targeting iron, or its regulatory pathways, as potential promising anticancer strategies for human therapy. Iron chelators, such as deferoxamine or iron-oxide-based nanoparticles, which are already tested in clinical trials, alone or in combination with chemotherapy, are also reported.

Keywords:  cancer; diagnostic; iron homeostasis; prognostic; therapy

DOI:  https://doi.org/10.3390/cancers12123524
Genes Dev. 2020 Dec 01. 34(23-24): 1577-1598

Stresses in the metastatic cascade: molecular mechanisms and therapeutic opportunities.

Minhong Shen, Yibin Kang.

  Metastasis is the ultimate "survival of the fittest" test for cancer cells, as only a small fraction of disseminated tumor cells can overcome the numerous hurdles they encounter during the transition from the site of origin to a distinctly different distant organ in the face of immune and therapeutic attacks and various other stresses. During cancer progression, tumor cells develop a variety of mechanisms to cope with the stresses they encounter, and acquire the ability to form metastases. Restraining these stress-releasing pathways could serve as potentially effective strategies to prevent or reduce metastasis and improve the survival of cancer patients. Here, we provide an overview of the tumor-intrinsic, microenvironment- and treatment-induced stresses that tumor cells encounter in the metastatic cascade and the molecular pathways they develop to relieve these stresses. We also summarize the preclinical and clinical studies that evaluate the potential therapeutic benefit of targeting these stress-relieving pathways.

Keywords:  cancer therapeutics; metastasis; stress; tumor microenvironment

DOI:  https://doi.org/10.1101/gad.343251.120
Cancers (Basel). 2020 Dec 02. pii: E3609. [Epub ahead of print]12(12):

NRF2 and the Ambiguous Consequences of Its Activation during Initiation and the Subsequent Stages of Tumourigenesis.

Holly Robertson, Albena T Dinkova-Kostova, John D Hayes.

  NF-E2 p45-related factor 2 (NRF2, encoded in the human by NFE2L2) mediates short-term adaptation to thiol-reactive stressors. In normal cells, activation of NRF2 by a thiol-reactive stressor helps prevent, for a limited period of time, the initiation of cancer by chemical carcinogens through induction of genes encoding drug-metabolising enzymes. However, in many tumour types, NRF2 is permanently upregulated. In such cases, its overexpressed target genes support the promotion and progression of cancer by suppressing oxidative stress, because they constitutively increase the capacity to scavenge reactive oxygen species (ROS), and they support cell proliferation by increasing ribonucleotide synthesis, serine biosynthesis and autophagy. Herein, we describe cancer chemoprevention and the discovery of the essential role played by NRF2 in orchestrating protection against chemical carcinogenesis. We similarly describe the discoveries of somatic mutations in NFE2L2 and the gene encoding the principal NRF2 repressor, Kelch-like ECH-associated protein 1 (KEAP1) along with that encoding a component of the E3 ubiquitin-ligase complex Cullin 3 (CUL3), which result in permanent activation of NRF2, and the recognition that such mutations occur frequently in many types of cancer. Notably, mutations in NFE2L2, KEAP1 and CUL3 that cause persistent upregulation of NRF2 often co-exist with mutations that activate KRAS and the PI3K-PKB/Akt pathway, suggesting NRF2 supports growth of tumours in which KRAS or PKB/Akt are hyperactive. Besides somatic mutations, NRF2 activation in human tumours can occur by other means, such as alternative splicing that results in a NRF2 protein which lacks the KEAP1-binding domain or overexpression of other KEAP1-binding partners that compete with NRF2. Lastly, as NRF2 upregulation is associated with resistance to cancer chemotherapy and radiotherapy, we describe strategies that might be employed to suppress growth and overcome drug resistance in tumours with overactive NRF2.

Keywords:  ATF4; Cullin 3; KEAP1; NADPH generation; NRF2; adaptation; antioxidant; autophagy; bioactivation; bladder; chemoprevention; chemotherapy; colon; drug metabolism; drug resistance; glutathione; head and neck; initiation; liver; lung; metastasis; oesophagus; oncogene; oxidative stress; pentose phosphate pathway; progression; proteasome; quinone-containing drugs; reactive oxygen species; rectum; recurrent disease; stomach; thioredoxin; tumour suppressor

DOI:  https://doi.org/10.3390/cancers12123609
Cell Res. 2020 Dec 02.

Ferroptosis: molecular mechanisms and health implications.

Daolin Tang, Xin Chen, Rui Kang, Guido Kroemer.

Cell death can be executed through different subroutines. Since the description of ferroptosis as an iron-dependent form of non-apoptotic cell death in 2012, there has been mounting interest in the process and function of ferroptosis. Ferroptosis can occur through two major pathways, the extrinsic or transporter-dependent pathway and the intrinsic or enzyme-regulated pathway. Ferroptosis is caused by a redox imbalance between the production of oxidants and antioxidants, which is driven by the abnormal expression and activity of multiple redox-active enzymes that produce or detoxify free radicals and lipid oxidation products. Accordingly, ferroptosis is precisely regulated at multiple levels, including epigenetic, transcriptional, posttranscriptional and posttranslational layers. The transcription factor NFE2L2 plays a central role in upregulating anti-ferroptotic defense, whereas selective autophagy may promote ferroptotic death. Here, we review current knowledge on the integrated molecular machinery of ferroptosis and describe how dysregulated ferroptosis is involved in cancer, neurodegeneration, tissue injury, inflammation, and infection.

DOI: https://doi.org/10.1038/s41422-020-00441-1
Mol Cell. 2020 Dec 03. pii: S1097-2765(20)30800-5. [Epub ahead of print]80(5): 760-761

The Center Cannot Hold: NRF2 Battles Ferroptosis in the 3rd Dimension.

Warren L Wu, Thales Papagiannakopoulos.

Takahashi et al. (2020) conduct a focused CRISPR/Cas9 screen against NRF2 target and other redox regulatory genes in both 2D- and 3D-culture systems, uncovering a vulnerability of spheroid cancer cells deprived of extracellular matrix to undergo ferroptosis.

DOI: https://doi.org/10.1016/j.molcel.2020.11.022
Metabolites. 2020 Dec 01. pii: E494. [Epub ahead of print]10(12):

Metabolic Drug Response Phenotyping in Colorectal Cancer Organoids by LC-QTOF-MS.

Sylvia K Neef, Nicole Janssen, Stefan Winter, Svenja K Wallisch, Ute Hofmann, Marc H Dahlke, Matthias Schwab, Thomas E Mürdter, Mathias Haag.

  As metabolic rewiring is crucial for cancer cell proliferation, metabolic phenotyping of patient-derived organoids is desirable to identify drug-induced changes and trace metabolic vulnerabilities of tumor subtypes. We established a novel protocol for metabolomic and lipidomic profiling of colorectal cancer organoids by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) facing the challenge of capturing metabolic information from a minimal sample amount (<500 cells/injection) in the presence of an extracellular matrix (ECM). The best procedure of the tested protocols included ultrasonic metabolite extraction with acetonitrile/methanol/water (2:2:1, v/v/v) without ECM removal. To eliminate ECM-derived background signals, we implemented a data filtering procedure based on the p-value and fold change cut-offs, which retained features with signal intensities >120% compared to matrix-derived signals present in blank samples. As a proof-of-concept, the method was applied to examine the early metabolic response of colorectal cancer organoids to 5-fluorouracil treatment. Statistical analysis revealed dose-dependent changes in the metabolic profiles of treated organoids including elevated levels of 2'-deoxyuridine, 2'-O-methylcytidine, inosine and 1-methyladenosine and depletion of 2'-deoxyadenosine and specific phospholipids. In accordance with the mechanism of action of 5-fluorouracil, changed metabolites are mainly involved in purine and pyrimidine metabolism. The novel protocol provides a first basis for the assessment of metabolic drug response phenotypes in 3D organoid models.

Keywords:  LC-MS; QTOF; colorectal cancer; lipidomics; metabolic profiling; metabolomics; organoids

DOI:  https://doi.org/10.3390/metabo10120494