bims-glucam 2022-02-13 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022–02–13
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

Targeting fuel pocket of cancer cell metabolism: A focus on glutaminolysis.
Deferoxamine Counteracts Cisplatin Resistance in A549 Lung Adenocarcinoma Cells by Increasing Vulnerability to Glutamine Deprivation-Induced Cell Death.
A Novel Glutamine Metabolism-Related Gene Signature in Prognostic Prediction of Osteosarcoma.
A mechanistic modeling framework reveals the key principles underlying tumor metabolism.
Spatially resolved isotope tracing reveals tissue metabolic activity.
Glutamine Metabolism-Regulated Nanoparticles to Enhance Chemoimmunotherapy by Increasing Antigen Presentation Efficiency.
The hallmarks of cancer metabolism: Still emerging.
Personalized Medicine for Prostate Cancer: Is Targeting Metabolism a Reality?
MYC promotes tyrosine kinase inhibitor resistance in ROS1 fusion-positive lung cancer.
Amino acid restriction induces a long non-coding RNA UBA6-AS1 to regulate GCN2-mediated integrated stress response in breast cancer.
Telaglenastat Plus Cabozantinib or Everolimus For Advanced or Metastatic Renal Cell Carcinoma: an Open-Label Phase 1 Trial.
Cancer-cell-derived GABA promotes β-catenin-mediated tumour growth and immunosuppression.
Glutamine synthetase licenses APC/C-mediated mitotic progression to drive cell growth.
Disrupting the MYC-TFEB Circuit Impairs Amino Acid Homeostasis and Provokes Metabolic Anergy.
Expression of gamma-glutamyltransferase 1 in glioblastoma cells confers resistance to cystine deprivation-induced ferroptosis.
INTEGRATE: Model-based multi-omics data integration to characterize multi-level metabolic regulation.
Targeting OXPHOS and the electronic transport chain in cancer; molecular and therapeutic implications.

Biochem Pharmacol. 2022 Feb 04. pii: S0006-2952(22)00037-5. [Epub ahead of print] 114943

Targeting fuel pocket of cancer cell metabolism: A focus on glutaminolysis.

Shagun Sharma, Navneet Agnihotri, Sandeep Kumar.

  Advances in cell metabolism over the past few decades have demonstrated glutamine as an essential nutrient for cancer cell survival and proliferation. Glutamine offers a remarkable capacity to fuel diverse metabolic pathways in cancer cells including the Krebs cycle, maintenance of redox homeostasis, and synthesis of cellular building blocks such as nucleic acids, fatty acids, glutathione, and other amino acids. The increase in glutaminolysis has further been linked to the accumulation of oncometabolites such as 2HG (2-Hydroxyglutarate), succinate, fumarate, etc., thereby contributing to tumorigenesis via regulating epigenetic modification of imprinted genes. Therefore, therapeutic targeting of glutaminolysis in cancer cells is worth exploring for possible treatment strategies for cancer management. In this review, we have discussed the detailed mechanism of glutamine uptake, transport, and its instrumental role in rewiring the metabolic adaptation of cancer cells in the tumor microenvironment under nutrient deprivation and hypoxia. Furthermore, we have attempted to provide an updated therapeutic intervention of glutamine metabolism as a treatment strategy for cancer management.

Keywords:  Cancer Cell Metabolism; Glutamine; Glutaminolysis; Tumor Microenvironment, Chemotherapy

DOI:  https://doi.org/10.1016/j.bcp.2022.114943
Front Oncol. 2021 ;11 794735

Deferoxamine Counteracts Cisplatin Resistance in A549 Lung Adenocarcinoma Cells by Increasing Vulnerability to Glutamine Deprivation-Induced Cell Death.

Wen-Jun Liu, Peng-Yu Pan, Ye Sun, Jian-Bo Wang, Huan Zhou, Xin Xie, Zhi-Yuan Duan, Han-Yu Dong, Wen-Na Chen, Li-de Zhang, Chun Wang.

  Glutamine, like glucose, is a major nutrient consumed by cancer cells, yet these cells undergo glutamine starvation in the cores of tumors, forcing them to evolve adaptive metabolic responses. Pharmacologically targeting glutamine metabolism or withdrawal has been exploited for therapeutic purposes, but does not always induce cancer cell death. The mechanism by which cancer cells adapt to resist glutamine starvation in cisplatin-resistant non-small-cell lung cancer (NSCLC) also remains uncertain. Here, we report the potential metabolic vulnerabilities of A549/DDP (drug-resistant human lung adenocarcinoma cell lines) cells, which were more easily killed by the iron chelator deferoxamine (DFO) during glutamine deprivation than their parental cisplatin-sensitive A549 cells. We demonstrate that phenotype resistance to cisplatin is accompanied by adaptive responses during glutamine deprivation partly via higher levels of autophagic activity and apoptosis resistance characteristics. Moreover, this adaptation could be explained by sustained glucose instead of glutamine-dominant complex II-dependent oxidative phosphorylation (OXPHOS). Further investigation revealed that cisplatin-resistant cells sustain OXPHOS partly via iron metabolism reprogramming during glutamine deprivation. This reprogramming might be responsible for mitochondrial iron-sulfur [Fe-S] cluster biogenesis, which has become an "Achilles' heel," rendering cancer cells vulnerable to DFO-induced autophagic cell death and apoptosis through c-Jun N-terminal kinase (JNK) signaling. Finally, in vivo studies using xenograft mouse models also confirmed the growth-slowing effect of DFO. In summary, we have elucidated the adaptive responses of cisplatin-resistant NSCLC cells, which balanced stability and plasticity to overcome metabolic reprogramming and permitted them to survive under stress induced by chemotherapy or glutamine starvation. In addition, for the first time, we show that suppressing the growth of cisplatin-resistant NSCLC cells via iron chelator-induced autophagic cell death and apoptosis was possible with DFO treatment. These findings provide a solid basis for targeting mitochondria iron metabolism in cisplatin-resistant NSCLC for therapeutic purposes, and it is plausible to consider that DFO facilitates in the improvement of treatment responses in cisplatin-resistant NSCLC patients.

Keywords:  NSCLC; cell death; cisplatin resistance; deferoxamine; glutamine deprivation; metabolic reprogramming

DOI:  https://doi.org/10.3389/fonc.2021.794735
Int J Gen Med. 2022 ;15 997-1011

A Novel Glutamine Metabolism-Related Gene Signature in Prognostic Prediction of Osteosarcoma.

Lu Wan, Wenchao Zhang, Zhongyue Liu, Zhimin Yang, Chao Tu, Zhihong Li.

   Purpose: Metabolic reprogramming, as one of the hallmarks of cancer, shows promising translational potential for cancer diagnosis, treatment and prognostic prediction. This study aims to construct and validate a prognostic prediction model for osteosarcoma based on glutamine metabolism-related genes.
Materials and Methods: A group of glutamine metabolism-related genes was identified from a public database and intersected with a list of osteosarcoma survival-related genes, and a risk score model based on sixteen glutamine metabolism-related genes was developed by using LASSO penalized Cox regression analysis.
Results: The prognosis of patients in the high-risk group was significantly worse than that of patients in the low-risk group in the training dataset (high- vs low-risk, 5-year overall survival: 11% vs 88%, p < 0.0001) and in two other external validation cohorts (high- vs low-risk, 5-year overall survival: 39% vs 81%, p = 0.015; 50% vs 94%, p = 0.011).In addition, a novel nomogram was constructed by integrating the risk score and clinical characteristics, including age, sex, metastasis status and chemotherapy response. This nomogram had superior predictive power compared with a nomogram composed of only conventional factors. Gene set enrichment analysis indicated that several well-known malignancy-associated gene sets, including MYC targets V1, DNA repair, and unfolded protein response, were enriched in the high-risk subgroup.
Conclusion: A novel glutamine metabolism-related prognostic prediction model and nomogram for osteosarcoma was developed and validated in the present study, which could predict the survival of patients with osteosarcoma and may facilitate individualized clinical decision-making for patients.

Keywords:  amino acid metabolism; bone tumor; nomogram; survivorship

DOI:  https://doi.org/10.2147/IJGM.S352859
PLoS Comput Biol. 2022 Feb 11. 18(2): e1009841

A mechanistic modeling framework reveals the key principles underlying tumor metabolism.

Shubham Tripathi, Jun Hyoung Park, Shivanand Pudakalakatti, Pratip K Bhattacharya, Benny Abraham Kaipparettu, Herbert Levine.

While aerobic glycolysis, or the Warburg effect, has for a long time been considered a hallmark of tumor metabolism, recent studies have revealed a far more complex picture. Tumor cells exhibit widespread metabolic heterogeneity, not only in their presentation of the Warburg effect but also in the nutrients and the metabolic pathways they are dependent on. Moreover, tumor cells can switch between different metabolic phenotypes in response to environmental cues and therapeutic interventions. A framework to analyze the observed metabolic heterogeneity and plasticity is, however, lacking. Using a mechanistic model that includes the key metabolic pathways active in tumor cells, we show that the inhibition of phosphofructokinase by excess ATP in the cytoplasm can drive a preference for aerobic glycolysis in fast-proliferating tumor cells. The differing rates of ATP utilization by tumor cells can therefore drive heterogeneity with respect to the presentation of the Warburg effect. Building upon this idea, we couple the metabolic phenotype of tumor cells to their migratory phenotype, and show that our model predictions are in agreement with previous experiments. Next, we report that the reliance of proliferating cells on different anaplerotic pathways depends on the relative availability of glucose and glutamine, and can further drive metabolic heterogeneity. Finally, using treatment of melanoma cells with a BRAF inhibitor as an example, we show that our model can be used to predict the metabolic and gene expression changes in cancer cells in response to drug treatment. By making predictions that are far more generalizable and interpretable as compared to previous tumor metabolism modeling approaches, our framework identifies key principles that govern tumor cell metabolism, and the reported heterogeneity and plasticity. These principles could be key to targeting the metabolic vulnerabilities of cancer.

DOI: https://doi.org/10.1371/journal.pcbi.1009841
Nat Methods. 2022 Feb;19(2): 223-230

Spatially resolved isotope tracing reveals tissue metabolic activity.

Lin Wang, Xi Xing, Xianfeng Zeng, S RaElle Jackson, Tara TeSlaa, Osama Al-Dalahmah, Laith Z Samarah, Katharine Goodwin, Lifeng Yang, Melanie R McReynolds, Xiaoxuan Li, Jeremy J Wolff, Joshua D Rabinowitz, Shawn M Davidson.

Isotope tracing has helped to determine the metabolic activities of organs. Methods to probe metabolic heterogeneity within organs are less developed. We couple stable-isotope-labeled nutrient infusion to matrix-assisted laser desorption ionization imaging mass spectrometry (iso-imaging) to quantitate metabolic activity in mammalian tissues in a spatially resolved manner. In the kidney, we visualize gluconeogenic flux and glycolytic flux in the cortex and medulla, respectively. Tricarboxylic acid cycle substrate usage differs across kidney regions; glutamine and citrate are used preferentially in the cortex and fatty acids are used in the medulla. In the brain, we observe spatial gradations in carbon inputs to the tricarboxylic acid cycle and glutamate under a ketogenic diet. In a carbohydrate-rich diet, glucose predominates throughout but in a ketogenic diet, 3-hydroxybutyrate contributes most strongly in the hippocampus and least in the midbrain. Brain nitrogen sources also vary spatially; branched-chain amino acids contribute most in the midbrain, whereas ammonia contributes in the thalamus. Thus, iso-imaging can reveal the spatial organization of metabolic activity.

DOI: https://doi.org/10.1038/s41592-021-01378-y
ACS Appl Mater Interfaces. 2022 Feb 09.

Glutamine Metabolism-Regulated Nanoparticles to Enhance Chemoimmunotherapy by Increasing Antigen Presentation Efficiency.

Bin Du, Qingqing Jiao, Yimeng Bai, Min Yu, Mengxue Pang, Mengmeng Zhao, Huizhen Ma, Hanchun Yao.

  Although the strategies to induce dendritic cells (DCs) maturation and promote their antigen presentation can stimulate the tumor immune response, the endogenous deficiency and immunosuppression of DCs reduce antigen utilization, which limits antigen presentation efficiency and reduces immunotherapy effectiveness. Here, we report an endogenous stimulus-responsive nanodelivery system (DOX@HFn-MSO@PGZL). On the one hand, doxorubicin (DOX) promoted antigen presentation by DCs after the immunogenic death of tumor cells. On the other hand, l-methionine sulfoximine (MSO) regulated the glutamine metabolism of tumor-associated macrophages (TAMs) to induce a shift toward the M1-type. M1-TAMs synergistically presented antigens with mature DCs and were more frequently produced to destroy the tumor suppressive immune microenvironment, resulting in the alleviation of DCs functional inhibition. Ultimately, the antigen presentation efficiency was improved, completely activating tumor immunity and exhibiting powerful antitumor effects.

Keywords:  antigen presentation; chemoimmunotherapy; glutamine metabolism; immune activation; immunogenic cell death

DOI:  https://doi.org/10.1021/acsami.1c21417
Cell Metab. 2022 Feb 01. pii: S1550-4131(22)00022-5. [Epub ahead of print]

The hallmarks of cancer metabolism: Still emerging.

Natalya N Pavlova, Jiajun Zhu, Craig B Thompson.

Metabolism of cancer cells is geared toward biomass production and proliferation. Since the metabolic resources within the local tissue are finite, this can lead to nutrient depletion and accumulation of metabolic waste. To maintain growth in these conditions, cancer cells employ a variety of metabolic adaptations, the nature of which is collectively determined by the physiology of their cell of origin, the identity of transforming lesions, and the tissue in which cancer cells reside. Furthermore, select metabolites not only serve as substrates for energy and biomass generation, but can also regulate gene and protein expression and influence the behavior of non-transformed cells in the tumor vicinity. As they grow and metastasize, tumors can also affect and be affected by the nutrient distribution within the body. In this hallmark update, recent advances are incorporated into a conceptual framework that may help guide further research efforts in exploring cancer cell metabolism.

DOI: https://doi.org/10.1016/j.cmet.2022.01.007
Front Oncol. 2021 ;11 778761

Personalized Medicine for Prostate Cancer: Is Targeting Metabolism a Reality?

Gio Fidelito, Matthew J Watt, Renea A Taylor.

  Prostate cancer invokes major shifts in gene transcription and metabolic signaling to mediate alterations in nutrient acquisition and metabolic substrate selection when compared to normal tissues. Exploiting such metabolic reprogramming is proposed to enable the development of targeted therapies for prostate cancer, yet there are several challenges to overcome before this becomes a reality. Herein, we outline the role of several nutrients known to contribute to prostate tumorigenesis, including fatty acids, glucose, lactate and glutamine, and discuss the major factors contributing to variability in prostate cancer metabolism, including cellular heterogeneity, genetic drivers and mutations, as well as complexity in the tumor microenvironment. The review draws from original studies employing immortalized prostate cancer cells, as well as more complex experimental models, including animals and humans, that more accurately reflect the complexity of the in vivo tumor microenvironment. In synthesizing this information, we consider the feasibility and potential limitations of implementing metabolic therapies for prostate cancer management.

Keywords:  lipid metabolism; metabolic heterogeneity; metabolic targeting; metabolism; obesity; patient-derived xenograft; prostate neoplasia

DOI:  https://doi.org/10.3389/fonc.2021.778761
Mol Cancer Res. 2022 Feb 11. pii: molcanres.MCR-22-0025-E.2022. [Epub ahead of print]

MYC promotes tyrosine kinase inhibitor resistance in ROS1 fusion-positive lung cancer.

Sudarshan R Iyer, Igor Odintsov, Adam J Schoenfeld, Evan Siau, Marissa S Mattar, Elisa de Stanchina, Inna Khodos, Alexander Drilon, Gregory J Riely, Marc Ladanyi, Romel Somwar, Monika A Davare.

Targeted therapy of ROS1 fusion-driven non-small cell lung cancer (NSCLC) has achieved notable clinical success. Despite this, resistance to therapy inevitably poses a significant challenge. MYC amplification was present in ~19% of lorlatinib-resistant ROS1-driven NSCLC. We hypothesized that MYC overexpression drives ROS1-TKI resistance. Using complementary approaches in multiple models, including a MYC-amplified patient-derived cell line and xenograft (LUAD-0006), we established that MYC overexpression induces broad ROS1 TKI resistance. Pharmacological inhibition of ROS1 combined with MYC knockdown were essential to completely suppress LUAD-0006 cell proliferation compared to either treatment alone. We interrogated cellular signaling in ROS1-TKI resistant LUAD-0006 and discovered significant differential regulation of targets associated with cell cycle, apoptosis, and mitochondrial function. Combinatorial treatment of mitochondrial inhibitors with crizotinib revealed inhibitory synergism, suggesting increased reliance on glutamine metabolism and fatty-acid synthesis in chronic ROS1-TKI treated LUAD-0006 cells. In vitro experiments further revealed that CDK4/6 and BET bromodomain inhibitors effectively mitigate ROS1 TKI resistance in MYC-overexpressing cells. Notably, in vivo studies demonstrate that tumor control may be regained by combining ROS1 TKI and CDK4/6 inhibition. Our results contribute to the broader understanding of ROS1-TKI resistance in NSCLC. Implications: This study functionally characterizes MYC overexpression as a novel form of therapeutic resistance to ROS1 tyrosine kinase inhibitors in non-small-cell lung cancer and proposes rational combination treatment strategies.

DOI: https://doi.org/10.1158/1541-7786.MCR-22-0025
FASEB J. 2022 Mar;36(3): e22201

Amino acid restriction induces a long non-coding RNA UBA6-AS1 to regulate GCN2-mediated integrated stress response in breast cancer.

Yi-Zhen Wu, Yi-Hsuan Chen, Chun-Ting Cheng, David K Ann, Ching-Ying Kuo.

  Oncogene activation, massive proliferation, and increased nutrient demands often result in nutrient and oxygen deprivation in solid tumors including breast cancer (BC), leading to the induction of oxidative stress and endoplasmic reticulum (ER) stress, and subsequently triggering integrated stress response (ISR). To elucidate the role of long non-coding RNAs (lncRNAs) in the ISR of BC, we performed transcriptome analyses and identified a lncRNA, UBA6-AS1, which was upregulated upon amino acid deprivation and ER stress. UBA6-AS1 was preferentially induced in triple-negative BC (TNBC) cells deprived of arginine or glutamine, two critical amino acids required for cancer cell growth, or treated with ER stress inducers. Mechanistically, UBA6-AS1 was regulated through the GCN2/eIF2α/ATF4 pathway, one of the major routes mediating ISR in amino acid sensing. In addition, both in vitro and in vivo assays indicated that UBA6-AS1 promoted TNBC cell survival when cells encountered metabolic stress, implicating a regulatory role of UBA6-AS1 in response to intratumoral metabolic stress during tumor progression. Moreover, PARP1 expression and activity were positively regulated by the GCN2/UBA6-AS1 axis upon amino acid deprivation. In conclusion, our data suggest that UBA6-AS1 is a novel lncRNA regulating ISR upon metabolic stress induction to promote TNBC cell survival. Furthermore, the GCN2-ATF4 axis is important for UBA6-AS1 induction to enhance PARP1 activity and could serve as a marker for the susceptibility of PARP inhibitors in TNBC.

Keywords:   UBA6-AS1 ; UBA6-DT ; PARP1; amino acid restriction; integrated stress response; long non-coding RNA

DOI:  https://doi.org/10.1096/fj.202101466R
Clin Cancer Res. 2022 Feb 09. pii: clincanres.2972.2021. [Epub ahead of print]

Telaglenastat Plus Cabozantinib or Everolimus For Advanced or Metastatic Renal Cell Carcinoma: an Open-Label Phase 1 Trial.

Funda Meric-Bernstam, Nizar M Tannir, Othon Lliopoulos, Richard J Lee, Melinda L Telli, Alice C Fan, Angela DeMichele, Naomi B Haas, Manish R Patel, James J Harding, Martin H Voss, Taofeek K Owonikoko, Bradley Carthon, Ramaprasad Srinivasan, Johanna C Bendell, Yonchu Jenkins, Sam H Whiting, Keith Orford, Mark K Bennett, Todd M Bauer.

PURPOSE: Dual inhibition of glucose and glutamine metabolism results in synergistic anti-cancer effects in solid tumor models. Telaglenastat, an investigational, small molecule, glutaminase inhibitor, exhibits modest single agent activity in RCC patients. This phase 1b trial evaluated telaglenastat plus cabozantinib or everolimus, agents known to impair glucose metabolism in patients with metastatic RCC (mRCC).
EXPERIMENTAL DESIGN: mRCC patients received escalating doses of telaglenastat (400-800mg per os [PO] twice daily) in a 3+3 design, plus either everolimus (10mg daily PO; TelaE) or cabozantinib (60mg daily PO; TelaC). Tumor response (RECISTv1.1) was assessed every 8 weeks. Endpoints included safety (primary) and anti-tumor activity.
RESULTS: 27 patients received TelaE, 13 received TelaC, with median 2 and 3 prior therapies, respectively. Treatment-related adverse events were mostly grade 1-2, most common including decreased appetite, anemia, elevated transaminases, and diarrhea with TelaE, and diarrhea, decreased appetite, elevated transaminases, and fatigue with TelaC. One dose-limiting toxicity occurred per cohort: grade 3 pruritic rash with TelaE and thrombocytopenia with TelaC. No MTD was reached for either combination, leading to a recommended phase 2 dose of 800mg telaglenastat BID with standard doses of E or C. TelaE disease control rate (DCR; response rate + stable disease) was 95.2% (20/21, including 1 partial response [PR]) among 21 patients with clear cell histology and 66.7% (2/3) for papillary. TelaC DCR was 100% (12/12) for both histologies (5/10 PRs as best response [3 confirmed] in clear cell).
CONCLUSIONS: TelaE and TelaC showed encouraging clinical activity and tolerability in heavily pre-treated mRCC patients.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-2972
Nat Cell Biol. 2022 Feb 10.

Cancer-cell-derived GABA promotes β-catenin-mediated tumour growth and immunosuppression.

De Huang, Yan Wang, J Will Thompson, Tao Yin, Peter B Alexander, Diyuan Qin, Poorva Mudgal, Haiyang Wu, Yaosi Liang, Lianmei Tan, Christopher Pan, Lifeng Yuan, Ying Wan, Qi-Jing Li, Xiao-Fan Wang.

Many cancers have an unusual dependence on glutamine. However, most previous studies have focused on the contribution of glutamine to metabolic building blocks and the energy supply. Here, we report that cancer cells with aberrant expression of glutamate decarboxylase 1 (GAD1) rewire glutamine metabolism for the synthesis of γ-aminobutyric acid (GABA)-a prominent neurotransmitter-in non-nervous tissues. An analysis of clinical samples reveals that increased GABA levels predict poor prognosis. Mechanistically, we identify a cancer-intrinsic pathway through which GABA activates the GABAB receptor to inhibit GSK-3β activity, leading to enhanced β-catenin signalling. This GABA-mediated β-catenin activation both stimulates tumour cell proliferation and suppresses CD8+ T cell intratumoural infiltration, such that targeting GAD1 or GABABR in mouse models overcomes resistance to anti-PD-1 immune checkpoint blockade therapy. Our findings uncover a signalling role for tumour-derived GABA beyond its classic function as a neurotransmitter that can be targeted pharmacologically to reverse immunosuppression.

DOI: https://doi.org/10.1038/s41556-021-00820-9
Nat Metab. 2022 Feb 10.

Glutamine synthetase licenses APC/C-mediated mitotic progression to drive cell growth.

Jiang-Sha Zhao, Shuo Shi, Hai-Yan Qu, Zuzana Keckesova, Zi-Jian Cao, Li-Xian Yang, Xiaofu Yu, Limin Feng, Zhong Shi, Joanna Krakowiak, Ruo-Ying Mao, Yi-Tong Shen, Yu-Meng Fan, Tian-Min Fu, Cunqi Ye, Daqian Xu, Xiaofei Gao, Jia You, Wenbo Li, Tingbo Liang, Zhimin Lu, Yu-Xiong Feng.

Tumors can reprogram the functions of metabolic enzymes to fuel malignant growth; however, beyond their conventional functions, key metabolic enzymes have not been found to directly govern cell mitosis. Here, we report that glutamine synthetase (GS) promotes cell proliferation by licensing mitotic progression independently of its metabolic function. GS depletion, but not impairment of its enzymatic activity, results in mitotic arrest and multinucleation across multiple lung and liver cancer cell lines, patient-derived organoids and xenografted tumors. Mechanistically, GS directly interacts with the nuclear pore protein NUP88 to prevent its binding to CDC20. Such interaction licenses activation of the CDC20-mediated anaphase-promoting complex or cyclosome to ensure proper metaphase-to-anaphase transition. In addition, GS is overexpressed in human non-small cell lung cancer and its depletion reduces tumor growth in mice and increases the efficacy of microtubule-targeted chemotherapy. Our findings highlight a moonlighting function of GS in governing mitosis and illustrate how an essential metabolic enzyme promotes cell proliferation and tumor development, beyond its main metabolic function.

DOI: https://doi.org/10.1038/s42255-021-00524-2
Cancer Res. 2022 Feb 11. pii: canres.1168.2021. [Epub ahead of print]

Disrupting the MYC-TFEB Circuit Impairs Amino Acid Homeostasis and Provokes Metabolic Anergy.

Mario R Fernandez, Franz X Schaub, Chunying Yang, Weimin Li, Seongseok Yun, Stephanie K Schaub, Frank C Dorsey, Min Liu, Meredith A Steeves, Andrea Ballabio, Alexandar Tzankov, Zhihua Chen, John M Koomen, Anders E Berglund, John L Cleveland.

MYC family oncoproteins are regulators of metabolic reprogramming that sustains cancer cell anabolism. Normal cells adapt to nutrient-limiting conditions by activating autophagy, which is required for amino acid (AA) homeostasis. Here we report that the autophagy pathway is suppressed by Myc in normal B cells, in premalignant and neoplastic B cells of Eμ-Myc transgenic mice, and in human MYC-driven Burkitt lymphoma. Myc suppresses autophagy by antagonizing the expression and function of transcription factor EB (TFEB), a master regulator of autophagy. Mechanisms that sustained AA pools in MYC-expressing B cells include coordinated induction of the proteasome and increases in AA transport. Reactivation of the autophagy-lysosomal pathway by TFEB disabled the malignant state by disrupting mitochondrial functions, proteasome activity, amino acid transport, and amino acid and nucleotide metabolism, leading to metabolic anergy, growth arrest and apoptosis. This phenotype provides therapeutic opportunities to disable MYC-driven malignancies, including AA restriction and treatment with proteasome inhibitors.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-1168
J Biol Chem. 2022 Feb 08. pii: S0021-9258(22)00143-0. [Epub ahead of print] 101703

Expression of gamma-glutamyltransferase 1 in glioblastoma cells confers resistance to cystine deprivation-induced ferroptosis.

Kazuki Hayashima, Hironori Katoh.

  Ferroptosis is an iron-dependent mode of cell death caused by excessive oxidative damage to lipids. Lipid peroxidation is normally suppressed by glutathione peroxidase 4, which requires reduced glutathione. Cystine is a major resource for glutathione synthesis, especially in cancer cells. Therefore, cystine deprivation or inhibition of cystine uptake promotes ferroptosis in cancer cells. However, the roles of other molecules involved in cysteine deprivation-induced ferroptosis are unexplored. We report here that the expression of gamma-glutamyltransferase 1 (GGT1), an enzyme that cleaves extracellular glutathione, determines the sensitivity of glioblastoma cells to cystine deprivation-induced ferroptosis at high cell density. In glioblastoma cells expressing GGT1, pharmacological inhibition or deletion of GGT1 suppressed the cell density-induced increase in intracellular glutathione levels and cell viability under cystine deprivation, which were restored by the addition of cysteinylglycine, the GGT product of glutathione cleavage. On the other hand, cystine deprivation induced glutathione depletion and ferroptosis in GGT1-deficient glioblastoma cells even at a high cell density. Exogenous expression of GGT1 in GGT1-deficient glioblastoma cells inhibited cystine deprivation-induced glutathione depletion and ferroptosis at a high cell density. This suggests that GGT1 plays an important role in glioblastoma cell survival under cystine-limited, high-cell density conditions. We conclude that combining GGT inhibitors with ferroptosis inducers may provide an effective therapeutic approach for treating glioblastoma.

Keywords:  amino acid; cell death; cell metabolism; cell surface enzyme; glioblastoma; glutathione

DOI:  https://doi.org/10.1016/j.jbc.2022.101703
PLoS Comput Biol. 2022 Feb 07. 18(2): e1009337

INTEGRATE: Model-based multi-omics data integration to characterize multi-level metabolic regulation.

Marzia Di Filippo, Dario Pescini, Bruno Giovanni Galuzzi, Marcella Bonanomi, Daniela Gaglio, Eleonora Mangano, Clarissa Consolandi, Lilia Alberghina, Marco Vanoni, Chiara Damiani.

Metabolism is directly and indirectly fine-tuned by a complex web of interacting regulatory mechanisms that fall into two major classes. On the one hand, the expression level of the catalyzing enzyme sets the maximal theoretical flux level (i.e., the net rate of the reaction) for each enzyme-controlled reaction. On the other hand, metabolic regulation controls the metabolic flux through the interactions of metabolites (substrates, cofactors, allosteric modulators) with the responsible enzyme. High-throughput data, such as metabolomics and transcriptomics data, if analyzed separately, do not accurately characterize the hierarchical regulation of metabolism outlined above. They must be integrated to disassemble the interdependence between different regulatory layers controlling metabolism. To this aim, we propose INTEGRATE, a computational pipeline that integrates metabolomics and transcriptomics data, using constraint-based stoichiometric metabolic models as a scaffold. We compute differential reaction expression from transcriptomics data and use constraint-based modeling to predict if the differential expression of metabolic enzymes directly originates differences in metabolic fluxes. In parallel, we use metabolomics to predict how differences in substrate availability translate into differences in metabolic fluxes. We discriminate fluxes regulated at the metabolic and/or gene expression level by intersecting these two output datasets. We demonstrate the pipeline using a set of immortalized normal and cancer breast cell lines. In a clinical setting, knowing the regulatory level at which a given metabolic reaction is controlled will be valuable to inform targeted, truly personalized therapies in cancer patients.

DOI: https://doi.org/10.1371/journal.pcbi.1009337
Semin Cancer Biol. 2022 Feb 02. pii: S1044-579X(22)00023-2. [Epub ahead of print]

Targeting OXPHOS and the electronic transport chain in cancer; molecular and therapeutic implications.

John Greene, Ashvina Segaran, Simon Lord.

  Oxidative phosphorylation (OXPHOS) takes place in mitochondria and is the process whereby cells use carbon fuels and oxygen to generate ATP. Formerly OXPHOS was thought to be reduced in tumours and that glycolysis was the critical pathway for generation of ATP but it is now clear that OXPHOS, at least in many tumour types, plays a critical role in delivering the bioenergetic and macromolecular anabolic requirements of cancer cells. There is now great interest in targeting the OXPHOS and the electron transport chain for cancer therapy and in this review article we describe current therapeutic approaches and challenges.

Keywords:  OXPHOS; cancer drugs; cancer metabolism; complex I; electron transport chain

DOI:  https://doi.org/10.1016/j.semcancer.2022.02.002