bims-glucam 2022-03-27 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022‒03‒27
nineteen papers selected by
Sreeparna Banerjee
Middle East Technical University

Circ_0001093 promotes glutamine metabolism and cancer progression of esophageal squamous cell carcinoma by targeting miR-579-3p/glutaminase axis.
Inhibition of lncRNA NEAT1 sensitizes medulloblastoma cells to cisplatin through modulating the miR-23a-3p-glutaminase (GLS) axis.
Roles of microRNAs in metabolic reprogramming of breast cancer.
Ginsenoside Rk1 regulates glutamine metabolism in hepatocellular carcinoma through inhibition of the ERK/c-Myc pathway.
Attenuation of glutamine synthetase selection marker improves product titer and reduces glutamine overflow in Chinese hamster ovary cells.
Reductive TCA cycle catalyzed by wild-type IDH2 promotes acute myeloid leukemia and is a metabolic vulnerability for potential targeted therapy.
Oncogenic viral infection and amino acid metabolism in cancer progression: Molecular insights and clinical implications.
Combined HP 13C Pyruvate and 13C-Glucose Fluxomic as a Potential Marker of Response to Targeted Therapies in YUMM1.7 Melanoma Xenografts.
Metabolic Reprogramming of Ovarian Cancer Spheroids during Adhesion.
Metabolic Profiling of Thymic Epithelial Tumors Hints to a Strong Warburg Effect, Glutaminolysis and Precarious Redox Homeostasis as Potential Therapeutic Targets.
Bcl-xL enforces a slow-cycling state necessary for survival in the nutrient-deprived microenvironment of pancreatic cancer.
Targeting Myc-driven stress vulnerability in mutant KRAS colorectal cancer.
Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis.
Multifaceted Roles of the KEAP1-NRF2 System in Cancer and Inflammatory Disease Milieu.
The central moTOR of metabolism.
Tumor Cell Glycolysis-At the Crossroad of Epithelial-Mesenchymal Transition and Autophagy.
Potential Metabolite Markers for Pancreatic Cancer Identified by Metabolomic Analysis of Induced Cancer-Associated Fibroblasts.
Targeting ferroptosis as a vulnerability in cancer.
Targeting an MDM2/MYC Axis to Overcome Drug Resistance in Multiple Myeloma.

J Bioenerg Biomembr. 2022 Mar 23.

Circ_0001093 promotes glutamine metabolism and cancer progression of esophageal squamous cell carcinoma by targeting miR-579-3p/glutaminase axis.

Cui-Juan Qian, Yi-Yang Tong, Yi-Chao Wang, Xiao-Sheng Teng, Jun Yao.

  Increasing studies indicate that circular RNAs (circRNAs) play critical roles in tumor metabolism of multiple cancers. However, the contribution of circRNAs in glutamine metabolism of esophageal squamous cell carcinoma (ESCC) remains elusive. The objective of this research was to investigate the role and mechanism of circRNA hsa_circ_0001093 (circ_0001093) in the glutamine metabolism and tumorigenesis of ESCC. Circ_0001093, microRNA-579-3p (miR-579-3p) and glutaminase (GLS) expressions in ESCC tissues and cell lines were measured by qRT-PCR, tissue array or Western blot. Cell proliferation, invasion and migration were assessed by CCK-8 or transwell assays. Glutamine consumption, glutamate and ATP production were detected by indicated assay kits. The relationships between circ_0001093 and miR-579-3p or GLS mRNA were investigated by bioinformatics analysis, RNA pull-down, luciferase reporter and RNA immunoprecipitation (RIP) assays. Here, we found that circ_0001093 expression was up-regulated in ESCC tissues and cell lines. Increased circ_0001093 expression predicted an unfavourable prognosis, and was associated with the lymph node metastasis, TNM staging and tumor size in ESCC tissues. Circ_0001093 knockdown suppressed cell proliferation, invasion, migration and glutamine metabolism of ESCC cells, while circ_0001093 over-expression showed the opposite effects. Mechanistically, circ_0001093 acted as a competing endogenous RNA (ceRNA) by sponging miR-579-3p, thereby increasing GLS expression. Furthermore, the inhibitory effects of circ_0001093 knockdown on the invasion, migration and glutamine metabolism were partly rescued by miR-579-3p inhibition or GLS over-expression in ESCC cells. Additionally, miR-579-3p expression was down-regulated in ESCC tissues, while GLS expression was up-regulated. In conclusion, this study first provides evidence that the circ_0001093/miR-579-3p/GLS regulatory network can affect glutamine metabolism and malignant phenotype of ESCC, which can further impact ESCC progression.

Keywords:  Circ_0001093; ESCC; Glutaminase; Tumor metabolism; miR-579-3p

DOI:  https://doi.org/10.1007/s10863-022-09935-6
Bioengineered. 2022 Mar;13(3): 7670-7682

Inhibition of lncRNA NEAT1 sensitizes medulloblastoma cells to cisplatin through modulating the miR-23a-3p-glutaminase (GLS) axis.

Jingjing Ge, Baohong Wang, Shuai Zhao, Jiaju Xu.

  Medulloblastoma (MB) is a commonly occurring brain malignancy in adolescence. Currently, the combination of chemotherapy with subsequent irradiation is a regular therapeutic strategy. However, high dosage of chemotherapy is associated with drug resistance and side effects. The long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1), which is frequently overexpressed in diverse human tumors, is correlated with worse survival rate in cancer patients. Currently, the precise roles of NEAT1 in MB and chemoresistance remain unclear. Our study aimed to investigate the biological functions of NEAT1 in cisplatin-resistant medulloblastoma. We report that NEAT1 was significantly upregulated in medulloblastoma patient specimens. Silencing NEAT1 significantly suppressed MB cell proliferation and sensitized MB cells to cisplatin. In cisplatin-resistant MB cell line, DAOY Cis R, NEAT1 expression, and glutamine metabolism were remarkably upregulated in cisplatin-resistant cells. Under low glutamine supply, cisplatin-resistant cells displayed increased cisplatin sensitivity. Bioinformatical analysis and luciferase assay uncovered that NEAT1 functions as a ceRNA of miR-23a-3p to downregulate its expressions in MB cells. Moreover, miR-23a-3p was apparently downregulated in MB patient tissues and cisplatin resistant MB cells. We identified GLS (glutaminase), a glutamine metabolism enzyme, was directly targeted by miR-23a-3p in MB cells. Rescue experiments demonstrated restoration of miR-23a-3p in NEAT1-overexpressing DAOY cisplatin resistant cells successfully overcame the NEAT1-promoted cisplatin resistance by targeting GLS. In general, our results revealed new molecular mechanisms for the lncRNA-NEAT1-mediated cisplatin sensitivity of MB.

Keywords:  Cisplatin resistance; glutaminase; glutamine metabolism; lncRNA NEAT1; miR-23a-3p

DOI:  https://doi.org/10.1080/21655979.2021.2008695
J Pak Med Assoc. 2022 Feb;72(2): 312-316

Roles of microRNAs in metabolic reprogramming of breast cancer.

Fan Feng, Qinqin Yu, Feng Zhang.

  Breast cancer cells exhibit deregulated metabolism. They require increased glucose uptake and glycolysis-associated enzymes to produce adenosine triphosphate by aerobic glycolysis rather than oxidative phosphorylation. Glutamine metabolism and fatty acid synthesis are also enhanced to meet the rapid and sustained cell growth. Triple-negative breast cancer and human epidermal growth factor receptor-2-positive breast cancers demonstrate significant metabolic reprogramming with increased levels of glucose and glutamine metabolism. Increasing evidences also suggest that micro-ribonucleic acids play important roles in the regulation of metabolic enzymes of breast cancer cells in post-transcriptional manner. Human epidermal growth factor receptor-2 and oestrogen receptor signalling pathways could have crosstalk with micro-ribonucleic acids in metabolic regulation network. The current narrative review was planned to go through recent advances on the role of micro-ribonucleic acids on metabolic reprogramming in breast cancer cells.

Keywords:   Breast cancer, Phenotype, miRNA, Metabolic reprogramming, Glycolysis, Glutamine.

DOI:  https://doi.org/10.47391/JPMA.1132
Food Funct. 2022 Mar 22.

Ginsenoside Rk1 regulates glutamine metabolism in hepatocellular carcinoma through inhibition of the ERK/c-Myc pathway.

Haoping Lu, Huayu Yin, Linlin Qu, Xiaoxuan Ma, Rongzhan Fu, Daidi Fan.

Hepatocellular carcinoma (HCC) is one of the most prevalent and deadly cancers in the world. Recently, suppression of glutamine metabolism has become one of the hottest therapy targets for cancer treatment. There is a growing amount of research that indicates that ginsenosides possess good anti-tumor activity. However, the effect of ginsenoside Rk1 on glutamine metabolism in HCC is unclear. In this study, Rk1 was demonstrated to be effective at inhibiting the proliferation of HCC through the induction of cell cycle arrest and apoptosis. Especially, Rk1 was shown for the first time to inhibit glutamine metabolism in HCC. Rk1 downregulates GLS1 expression, and consequently decreases the GSH production, stimulating ROS accumulation to induce apoptosis. In addition, transcriptomic results showed that the ERK/c-Myc signaling pathway was enriched in HepG2. Rk1 exerts an inhibitory effect on glutamine metabolism in HCC by regulating the ERK/c-Myc signaling pathway, and inducing apoptosis in vitro and in vivo with less toxicity. Therefore, ginsenoside Rk1 could be a promising candidate for the clinical treatment of HCC.

DOI: https://doi.org/10.1039/d1fo03728e
Biotechnol Bioeng. 2022 Mar 21.

Attenuation of glutamine synthetase selection marker improves product titer and reduces glutamine overflow in Chinese hamster ovary cells.

Sarah A Sacco, Angela M Tuckowski, Irina Trenary, Lauren Kraft, Michael J Betenbaugh, Jamey D Young, Kevin D Smith.

  The glutamine synthetase (GS) expression system is commonly used to ensure stable transgene integration and amplification in CHO host lines. Transfected cell populations are typically grown in the presence of the GS inhibitor, methionine sulfoximine (MSX), to further select for increased transgene copy number. However, high levels of GS activity produce excess glutamine. We hypothesized that attenuating the GS promoter while keeping the strong IgG promoter on the GS-IgG expression vector would result in a more efficient cellular metabolic phenotype. Herein, we characterized CHO cell lines expressing GS from either an attenuated promoter or an SV40 promoter and selected with/without MSX. CHO cells with the attenuated GS promoter had higher IgG specific productivity and lower glutamine production compared to cells with SV40-driven GS expression. Selection with MSX increased both specific productivity and glutamine production, regardless of GS promoter strength. 13 C metabolic flux analysis (MFA) was performed to further assess metabolic differences between these cell lines. Interestingly, central carbon metabolism was unaltered by the attenuated GS promoter while the fate of glutamate and glutamine varied depending on promoter strength and selection conditions. This study highlights the ability to optimize the GS expression system to improve IgG production and reduce wasteful glutamine overflow, without significantly altering central metabolism. Additionally, a detailed supplementary analysis of two "lactate runaway" reactors provides insight into the poorly understood phenomenon of excess lactate production by some CHO cell cultures. This article is protected by copyright. All rights reserved.

Keywords:  13C metabolic flux analysis; Chinese hamster ovary cells; Glutamine synthetase; Lactate runaway

DOI:  https://doi.org/10.1002/bit.28084
J Hematol Oncol. 2022 Mar 21. 15(1): 30

Reductive TCA cycle catalyzed by wild-type IDH2 promotes acute myeloid leukemia and is a metabolic vulnerability for potential targeted therapy.

Peiting Zeng, Wenhua Lu, Jingyu Tian, Shuang Qiao, Jiangjiang Li, Christophe Glorieux, Shijun Wen, Hui Zhang, Yiqing Li, Peng Huang.

  BACKGROUND: Isocitrate dehydrogenase-2 (IDH2) is a mitochondrial enzyme that catalyzes the metabolic conversion between isocitrate and alpha-ketoglutarate (α-KG) in the TCA cycle. IDH2 mutation is an oncogenic event in acute myeloid leukemia (AML) due to the generation of 2-hydroxyglutarate. However, the role of wild-type IDH2 in AML remains unknown, despite patients with it suffer worse clinical outcome than those harboring mutant type.METHODS: IDH2 expression in AML cell lines and patient samples was evaluated by RT-qPCR, western blotting and database analyses. The role of wild-type IDH2 in AML cell survival and proliferation was tested using genetic knockdown and pharmacological inhibition in AML cells and animal models. LC-MS, GC-MS, isotope metabolic tracing, and molecular analyses were performed to reveal the underlying mechanisms.
RESULTS: We found that wild-type IDH2 was overexpressed in AML and played a major role in promoting leukemia cell survival and proliferation in vitro and in vivo. Metabolomic analyses revealed an active IDH2-mediated reductive TCA cycle that promoted the conversion of α-KG to isocitrate/citrate to facilitate glutamine utilization for lipid synthesis in AML cells. Suppression of wild-type IDH2 by shRNA resulted in elevated α-KG and decreased isocitrate/citrate, leading to reduced lipid synthesis, a significant decrease in c-Myc downregulated by α-KG, and an inhibition of AML viability and proliferation. Importantly, pharmacological inhibition of IDH2 showed significant therapeutic effect in mice inoculated with AML cells with wt-IDH2 and induced a downregulation of C-MYC in vivo.
CONCLUSIONS: Wt-IDH2 is an essential molecule for AML cell survival and proliferation by promoting conversion of α-KG to isocitrate for lipid synthesis and by upregulating c-Myc expression and could be a potential therapeutic target in AML.

Keywords:  Acute myeloid leukemia; Alpha-ketoglutarate; Lipid synthesis; TCA cycle; Wild-type IDH2; c-Myc

DOI:  https://doi.org/10.1186/s13045-022-01245-z
Biochim Biophys Acta Rev Cancer. 2022 Mar 18. pii: S0304-419X(22)00049-X. [Epub ahead of print]1877(3): 188724

Oncogenic viral infection and amino acid metabolism in cancer progression: Molecular insights and clinical implications.

Na Liu, Feng Shi, Lifang Yang, Weihua Liao, Ya Cao.

  Viruses lack essential living system, so they must hijack host cell metabolism for its survival and reproduction. Interestingly, the metabolic reprogramming induced by oncovirus is critical for the malignant transformation. Amino acid can supply the source of nitrogen and carbon for biosynthesis or fulfill the energy requirement for the rapid growth of tumor cells. Amino acid metabolism caused by oncogenic viral infection often mirrors metabolic changes observed in cancer cells, such as glutamine addiction, asparagine dependence, arginine auxotrophy and active serine/ proline metabolism. In this review, we describe amino acid metabolism reprogramming in tumors. We also discuss how oncogenic viruses hijack amino acid metabolism in the stress status. Further research on the metabolic profile of virus-related cancers will not only provide new targets for tumor prevention and treatment, but novel diagnostic and therapeutic strategies as well.

Keywords:  Amino acid metabolism; Infection-related carcinogenesis; Metabolic reprogramming; Oncogenic virus

DOI:  https://doi.org/10.1016/j.bbcan.2022.188724
Biomedicines. 2022 Mar 19. pii: 717. [Epub ahead of print]10(3):

Combined HP 13C Pyruvate and 13C-Glucose Fluxomic as a Potential Marker of Response to Targeted Therapies in YUMM1.7 Melanoma Xenografts.

Chantale Farah, Marie-Aline Neveu, Caner Yelek, Caroline Bouzin, Bernard Gallez, Jean-François Baurain, Lionel Mignion, Bénédicte F Jordan.

  A vast majority of BRAF V600E mutated melanoma patients will develop resistance to combined BRAF/MEK inhibition after initial clinical response. Resistance to targeted therapy is described to be accompanied by specific metabolic changes in melanoma. The aim of this work was to evaluate metabolic imaging using 13C-MRS (Magnetic Resonance Spectroscopy) as a marker of response to BRAF/MEK inhibition in a syngeneic melanoma model. Tumor growth was significantly delayed in mice bearing YUMM1.7 melanoma xenografts treated with the BRAF inhibitor vemurafenib, and/or with the MEK inhibitor trametinib, in comparison with the control group. 13C-MRS was performed in vivo after injection of hyperpolarized (HP) 13C-pyruvate, at baseline and 24 h after treatment, to evaluate dynamic changes in pyruvate-lactate exchange. Furthermore, ex vivo 13C-MRS steady state metabolic tracing experiments were performed after U-13C-glucose or 5-13C-glutamine injection, 24 h after treatment. The HP 13C-lactate-to-pyruvate ratio was not modified in response to BRAF/MEK inhibition, whereas the production of 13C-lactate from 13C-glucose was significantly reduced 24 h after treatment with vemurafenib, trametinib, or with the combined inhibitors. Conversely, 13C-glutamine metabolism was not modified in response to BRAF/MEK inhibition. In conclusion, we identified 13C-glucose fluxomic as a potential marker of response to BRAF/MEK inhibition in YUMM1.7 melanoma xenografts.

Keywords:  13C-MRS; BRAF and MEK inhibition; markers of response; melanoma; targeted therapy; tumor metabolism

DOI:  https://doi.org/10.3390/biomedicines10030717
Cancers (Basel). 2022 Mar 09. pii: 1399. [Epub ahead of print]14(6):

Metabolic Reprogramming of Ovarian Cancer Spheroids during Adhesion.

Stephanie L E Compton, Joseph P Grieco, Benita Gollamudi, Eric Bae, Jennifer H Van Mullekom, Eva M Schmelz.

  Ovarian cancer remains a deadly disease and its recurrence disease is due in part to the presence of disseminating ovarian cancer aggregates not removed by debulking surgery. During dissemination in a dynamic ascitic environment, the spheroid cells' metabolism is characterized by low respiration and fragmented mitochondria, a metabolic phenotype that may not support secondary outgrowth after adhesion. Here, we investigated how adhesion affects cellular respiration and substrate utilization of spheroids mimicking early stages of secondary metastasis. Using different glucose and oxygen levels, we investigated cellular metabolism at early time points of adherence (24 h and less) comparing slow and fast-developing disease models. We found that adhesion over time showed changes in cellular energy metabolism and substrate utilization, with a switch in the utilization of mostly glutamine to glucose but no changes in fatty acid oxidation. Interestingly, low glucose levels had less of an impact on cellular metabolism than hypoxia. A resilience to culture conditions and the capacity to utilize a broader spectrum of substrates more efficiently distinguished the highly aggressive cells from the cells representing slow-developing disease, suggesting a flexible metabolism contributes to the stem-like properties. These results indicate that adhesion to secondary sites initiates a metabolic switch in the oxidation of substrates that could support outgrowth and successful metastasis.

Keywords:  glucose uptake; glutamine; hypoxia; metabolism; mitochondrial function; ovarian cancer; respiration; spheroid; sphingosine-1-phosphate; substrate utilization

DOI:  https://doi.org/10.3390/cancers14061399
Cancers (Basel). 2022 Mar 18. pii: 1564. [Epub ahead of print]14(6):

Metabolic Profiling of Thymic Epithelial Tumors Hints to a Strong Warburg Effect, Glutaminolysis and Precarious Redox Homeostasis as Potential Therapeutic Targets.

Mohammad Alwahsh, Robert Knitsch, Rosemarie Marchan, Jörg Lambert, Christian Hoerner, Xiaonan Zhang, Berthold Schalke, De-Hyung Lee, Elena Bulut, Thomas Graeter, German Ott, Katrin S Kurz, Gerhard Preissler, Sebastian Schölch, Joviana Farhat, Zhihan Yao, Carsten Sticht, Philipp Ströbel, Roland Hergenröder, Alexander Marx, Djeda Belharazem.

  Thymomas and thymic carcinomas (TC) are malignant thymic epithelial tumors (TETs) with poor outcome, if non-resectable. Metabolic signatures of TETs have not yet been studied and may offer new therapeutic options. Metabolic profiles of snap-frozen thymomas (WHO types A, AB, B1, B2, B3, n = 12) and TCs (n = 3) were determined by high resolution magic angle spinning 1H nuclear magnetic resonance (HRMAS 1H-NMR) spectroscopy. Metabolite-based prediction of active KEGG metabolic pathways was achieved with MetPA. In relation to metabolite-based metabolic pathways, gene expression signatures of TETs (n = 115) were investigated in the public "The Cancer Genome Atlas" (TCGA) dataset using gene set enrichment analysis. Overall, thirty-seven metabolites were quantified in TETs, including acetylcholine that was not previously detected in other non-endocrine cancers. Metabolite-based cluster analysis distinguished clinically indolent (A, AB, B1) and aggressive TETs (B2, B3, TCs). Using MetPA, six KEGG metabolic pathways were predicted to be activated, including proline/arginine, glycolysis and glutathione pathways. The activated pathways as predicted by metabolite-profiling were generally enriched transcriptionally in the independent TCGA dataset. Shared high lactic acid and glutamine levels, together with associated gene expression signatures suggested a strong "Warburg effect", glutaminolysis and redox homeostasis as potential vulnerabilities that need validation in a large, independent cohort of aggressive TETs. If confirmed, targeting metabolic pathways may eventually prove as adjunct therapeutic options in TETs, since the metabolic features identified here are known to confer resistance to cisplatin-based chemotherapy, kinase inhibitors and immune checkpoint blockers, i.e., currently used therapies for non-resectable TETs.

Keywords:  HRMAS 1H-NMR; biomarker; metabolomics; thymic carcinoma; thymoma

DOI:  https://doi.org/10.3390/cancers14061564
Cancer Res. 2022 Mar 22. pii: canres.CAN-22-0431-E.2022. [Epub ahead of print]

Bcl-xL enforces a slow-cycling state necessary for survival in the nutrient-deprived microenvironment of pancreatic cancer.

Yogev Sela, Jinyang Li, Shivahamy Maheswaran, Robert J Norgard, Salina Yuan, Maimon E Hubbi, Miriam Doepner, Jimmy P Xu, Elaine S Ho, Clementina Mesaros, Colin Sheehan, Grace Croley, Alexander Muir, Ian A Blair, Ophir Shalem, Chi V Dang, Ben Z Stanger.

Solid tumors possess heterogeneous metabolic microenvironments where oxygen and nutrient availability are plentiful ('fertile regions') or scarce ('arid regions'). While cancer cells residing in fertile regions proliferate rapidly, most cancer cells in vivo reside in arid regions and exhibit a slow-cycling state that renders them chemoresistant. Here, we developed an in vitro system enabling systematic comparison between these populations via transcriptome analysis, metabolomic profiling, and whole-genome CRISPR screening. Metabolic deprivation led to pronounced transcriptional and metabolic reprogramming, resulting in decreased anabolic activities and distinct vulnerabilities. Reductions in anabolic, energy-consuming activities, particularly cell proliferation, were not simply byproducts of the metabolic challenge but rather essential adaptations. Mechanistically, Bcl-xL played a central role in the adaptation to nutrient and oxygen deprivation. In this setting, Bcl-xL protected quiescent cells from the lethal effects of cell cycle entry in the absence of adequate nutrients. Moreover, inhibition of Bcl-xL combined with traditional chemotherapy had a synergistic anti-tumor effect that targeted cycling cells. Bcl-xL expression was strongly associated with poor patient survival despite being confined to the slow-cycling fraction of human pancreatic cancer cells. These findings provide a rationale for combining traditional cancer therapies that target rapidly cycling cells with those that target quiescent, chemoresistant cells associated with nutrient and oxygen deprivation.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-0431
Mol Biomed. 2022 Mar 21. 3(1): 10

Targeting Myc-driven stress vulnerability in mutant KRAS colorectal cancer.

Hang Ruan, Brian J Leibowitz, Yingpeng Peng, Lin Shen, Lujia Chen, Charlie Kuang, Robert E Schoen, Xinghua Lu, Lin Zhang, Jian Yu.

  Mutant KRAS is a key driver in colorectal cancer (CRC) and promotes Myc translation and Myc-dependent stress adaptation and proliferation. Here, we report that the combination of two FDA-approved drugs Bortezomib and Everolimus (RAD001) (BR) is highly efficacious against mutant KRAS CRC cells. Mechanistically, the combination, not single agent, rapidly depletes Myc protein, not mRNA, and leads to GCN2- and p-eIF2α-dependent cell death through the activation of extrinsic and intrinsic apoptotic pathways. Cell death is selectively induced in mutant KRAS CRC cells with elevated basal Myc and p-eIF2α and is characterized by CHOP induction and transcriptional signatures in proteotoxicity, oxidative stress, metabolic inhibition, and immune activation. BR-induced p-GCN2/p-eIF2α elevation and cell death are strongly attenuated by MYC knockdown and enhanced by MYC overexpression. The BR combination is efficacious against mutant KRAS patient derived organoids (PDO) and xenografts (PDX) by inducing p-eIF2α/CHOP and cell death. Interestingly, an elevated four-gene (DDIT3, GADD45B, CRYBA4 and HSPA1L) stress signature is linked to shortened overall survival in CRC patients. These data support that Myc-dependent stress adaptation drives the progression of mutant KRAS CRC and serves as a therapeutic vulnerability, which can be targeted using dual translational inhibitors.

Keywords:  Bortezomib; Colorectal cancer; Everolimus; Mutant KRAS; Myc; eIF2α

DOI:  https://doi.org/10.1186/s43556-022-00070-7
Viruses. 2022 Mar 14. pii: 602. [Epub ahead of print]14(3):

Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis.

Charles N S Allen, Sterling P Arjona, Maryline Santerre, Bassel E Sawaya.

  Metabolic reprogramming is a hallmark of cancer and has proven to be critical in viral infections. Metabolic reprogramming provides the cell with energy and biomass for large-scale biosynthesis. Based on studies of the cellular changes that contribute to metabolic reprogramming, seven main hallmarks can be identified: (1) increased glycolysis and lactic acid, (2) increased glutaminolysis, (3) increased pentose phosphate pathway, (4) mitochondrial changes, (5) increased lipid metabolism, (6) changes in amino acid metabolism, and (7) changes in other biosynthetic and bioenergetic pathways. Viruses depend on metabolic reprogramming to increase biomass to fuel viral genome replication and production of new virions. Viruses take advantage of the non-metabolic effects of metabolic reprogramming, creating an anti-apoptotic environment and evading the immune system. Other non-metabolic effects can negatively affect cellular function. Understanding the role metabolic reprogramming plays in viral pathogenesis may provide better therapeutic targets for antivirals.

Keywords:  Warburg effect; amino acid metabolism; biomass; biosynthetic and bioenergetic pathways; glutaminolysis; glycolysis; lipid metabolism; metabolic reprogramming; mitochondria; pentose phosphate pathway; viral replication; virus

DOI:  https://doi.org/10.3390/v14030602
Antioxidants (Basel). 2022 Mar 11. pii: 538. [Epub ahead of print]11(3):

Multifaceted Roles of the KEAP1-NRF2 System in Cancer and Inflammatory Disease Milieu.

Harit Panda, Huaichun Wen, Mikiko Suzuki, Masayuki Yamamoto.

  In a multicellular environment, many different types of cells interact with each other. The KEAP1-NRF2 system defends against electrophilic and oxidative stresses in various types of cells. However, the KEAP1-NRF2 system also regulates the expression of genes involved in cell proliferation and inflammation, indicating that the system plays cell type-specific roles. In this review, we introduce the multifarious roles of the KEAP1-NRF2 system in various types of cells, especially focusing on cancer and inflammatory diseases. Cancer cells frequently hijack the KEAP1-NRF2 system, and NRF2 activation confers cancer cells with a proliferative advantage and therapeutic resistance. In contrast, the activation of NRF2 in immune cells, especially in myeloid cells, suppresses tumor development. In chronic inflammatory diseases, such as sickle cell disease, NRF2 activation in myeloid and endothelial cells represses the expression of proinflammatory cytokine and adherent molecule genes, mitigating inflammation and organ damage. Based on these cell-specific roles played by the KEAP1-NRF2 system, NRF2 inducers have been utilized for the treatment of inflammatory diseases. In addition, the use of NRF2 inducers and/or inhibitors with canonical antineoplastic drugs is an emerging approach to cancer treatment.

Keywords:  KEAP1; NRF2; NRF2-addicted/activated cancer; cancer immunity; inflammation; sickle cell disease

DOI:  https://doi.org/10.3390/antiox11030538
Dev Cell. 2022 Mar 15. pii: S1534-5807(22)00126-5. [Epub ahead of print]

The central moTOR of metabolism.

Judith Simcox, Dudley W Lamming.

  The protein kinase mechanistic target of rapamycin (mTOR) functions as a central regulator of metabolism, integrating diverse nutritional and hormonal cues to control anabolic processes, organismal physiology, and even aging. This review discusses the current state of knowledge regarding the regulation of mTOR signaling and the metabolic regulation of the four macromolecular building blocks of the cell: carbohydrate, nucleic acid, lipid, and protein by mTOR. We review the role of mTOR in the control of organismal physiology and aging through its action in key tissues and discuss the potential for clinical translation of mTOR inhibition for the treatment and prevention of diseases of aging.

Keywords:  amino acids; lipids; mTOR; mTORC1; mTORC2; metabolism; protein; rapamycin

DOI:  https://doi.org/10.1016/j.devcel.2022.02.024
Cells. 2022 Mar 18. pii: 1041. [Epub ahead of print]11(6):

Tumor Cell Glycolysis-At the Crossroad of Epithelial-Mesenchymal Transition and Autophagy.

Fabrizio Marcucci, Cristiano Rumio.

  Upregulation of glycolysis, induction of epithelial-mesenchymal transition (EMT) and macroautophagy (hereafter autophagy), are phenotypic changes that occur in tumor cells, in response to similar stimuli, either tumor cell-autonomous or from the tumor microenvironment. Available evidence, herein reviewed, suggests that glycolysis can play a causative role in the induction of EMT and autophagy in tumor cells. Thus, glycolysis has been shown to induce EMT and either induce or inhibit autophagy. Glycolysis-induced autophagy occurs both in the presence (glucose starvation) or absence (glucose sufficiency) of metabolic stress. In order to explain these, in part, contradictory experimental observations, we propose that in the presence of stimuli, tumor cells respond by upregulating glycolysis, which will then induce EMT and inhibit autophagy. In the presence of stimuli and glucose starvation, upregulated glycolysis leads to adenosine monophosphate-activated protein kinase (AMPK) activation and autophagy induction. In the presence of stimuli and glucose sufficiency, upregulated glycolytic enzymes (e.g., aldolase or glyceraldehyde 3-phosphate dehydrogenase) or decreased levels of glycolytic metabolites (e.g., dihydroxyacetone phosphate) may mimic a situation of metabolic stress (herein referred to as "pseudostarvation"), leading, directly or indirectly, to AMPK activation and autophagy induction. We also discuss possible mechanisms, whereby glycolysis can induce a mixed mesenchymal/autophagic phenotype in tumor cells. Subsequently, we address unresolved problems in this field and possible therapeutic consequences.

Keywords:  AMPK; EMT; autophagy; glycolysis; mTOR; starvation

DOI:  https://doi.org/10.3390/cells11061041
Cancers (Basel). 2022 Mar 08. pii: 1375. [Epub ahead of print]14(6):

Potential Metabolite Markers for Pancreatic Cancer Identified by Metabolomic Analysis of Induced Cancer-Associated Fibroblasts.

Yoshihiro Miyazaki, Nobuhito Mori, Yuka Akagi, Tatsuya Oda, Yasuyuki S Kida.

  Cancer-associated fibroblasts (CAFs) in the tumor microenvironment perform glycolysis to produce energy, i.e., ATP. Since the origin of CAFs is unidentified, it is not determined whether the intracellular metabolism transitions from oxidative phosphorylation (OXPHOS) to glycolysis when normal tissue fibroblasts differentiate into CAFs. In this study, we established an experimental system and induced the in vitro differentiation of mesenchymal stem cells (MSCs) to CAFs. Additionally, we performed metabolomic and RNA-sequencing analyses before and after differentiation to investigate changes in the intracellular metabolism. Consequently, we discovered that OXPHOS, which was the primary intracellular metabolism in MSCs, was reprogrammed to glycolysis. Furthermore, we analyzed the metabolites in pancreatic tumor tissues in a mice model. The metabolites extracted as candidates in the in vitro experiments were also detected in the in vivo experiments. Thus, we conclude that normal tissue fibroblasts that differentiate into CAFs undergo a metabolic reprogramming from OXPHOS to glycolysis. Moreover, we identified the CAF-specific metabolites expressed during metabolic reprogramming as potential future biomarkers for pancreatic cancer.

Keywords:  cancer-associated fibroblasts; cell differentiation; glycolysis; intracellular metabolism; oxidative phosphorylation; pancreatic cancer; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers14061375
Nat Rev Cancer. 2022 Mar 25.

Targeting ferroptosis as a vulnerability in cancer.

Guang Lei, Li Zhuang, Boyi Gan.

Ferroptosis is an iron-dependent form of regulated cell death that is triggered by the toxic build-up of lipid peroxides on cellular membranes. In recent years, ferroptosis has garnered enormous interest in cancer research communities, partly because it is a unique cell death modality that is mechanistically and morphologically different from other forms of cell death, such as apoptosis, and therefore holds great potential for cancer therapy. In this Review, we summarize the current understanding of ferroptosis-inducing and ferroptosis defence mechanisms, dissect the roles and mechanisms of ferroptosis in tumour suppression and tumour immunity, conceptualize the diverse vulnerabilities of cancer cells to ferroptosis, and explore therapeutic strategies for targeting ferroptosis in cancer.

DOI: https://doi.org/10.1038/s41568-022-00459-0
Cancers (Basel). 2022 Mar 21. pii: 1592. [Epub ahead of print]14(6):

Targeting an MDM2/MYC Axis to Overcome Drug Resistance in Multiple Myeloma.

Omar Faruq, Davidson Zhao, Mariusz Shrestha, Andrea Vecchione, Eldad Zacksenhaus, Hong Chang.

  BACKGROUND: MDM2 is elevated in multiple myeloma (MM). Although traditionally, MDM2 negatively regulates p53, a growing body of research suggests that MDM2 plays several p53-independent roles in cancer pathogenesis as a regulator of oncogene mRNA stability and translation. Yet, the molecular mechanisms underlying MDM2 overexpression and its role in drug resistance in MM remain undefined.METHODS: Both myeloma cell lines and primary MM samples were employed. Cell viability, cell cycle and apoptosis assays, siRNA transfection, quantitative real-time PCR, immunoblotting, co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), soft agar colony formation and migration assay, pulse-chase assay, UV cross-linking, gel-shift assay, RNA-protein binding assays, MEME-analysis for discovering c-Myc DNA binding motifs studies, reporter gene constructs procedure, gene transfection and reporter assay, MM xenograft mouse model studies, and statistical analysis were applied in this study.
RESULTS: We show that MDM2 is associated with poor prognosis. Importantly, its upregulation in primary MM samples and human myeloma cell lines (HMCLs) drives drug resistance. Inhibition of MDM2 by RNAi, or by the MDM2/XIAP dual inhibitor MX69, significantly enhanced the sensitivity of resistant HMCLs and primary MM samples to bortezomib and other anti-myeloma drugs, demonstrating that MDM2 can modulate drug response. MDM2 inhibition resulted in a remarkable suppression of relapsed MM cell growth, colony formation, migration and induction of apoptosis through p53-dependent and -independent pathways. Mechanistically, MDM2 was found to reciprocally regulate c-Myc in MM; MDM2 binds to AREs on c-Myc 3'UTR to increase c-Myc mRNA stability and translation, while MDM2 is a direct transcriptional target of c-Myc. MDM2 inhibition rendered c-Myc mRNA unstable, and reduced c-Myc protein expression in MM cells. Importantly, in vivo delivery of MX69 in combination with bortezomib led to significant regression of tumors and prolonged survival in an MM xenograft model.
CONCLUSION: Our findings provide a rationale for the therapeutic targeting of MDM2/c-Myc axis to improve clinical outcome of patients with refractory/relapsed MM.

Keywords:  MDM2; MX69; c-Myc; drug resistance; multiple myeloma

DOI:  https://doi.org/10.3390/cancers14061592