bims-glucam 2023-07-02 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023‒07‒02
thirteen papers selected by
Sreeparna Banerjee
Middle East Technical University

c-Myc protects hepatocellular carcinoma cell from ferroptosis induced by glutamine deprivation via upregulating GOT1 and Nrf2.
Glutamine and amino acid metabolism as a prognostic signature and therapeutic target in endometrial cancer.
Mitochondrial uncoupling inhibits reductive carboxylation in cancer cells.
Critical role of antioxidant programs in enzalutamide-resistant prostate cancer.
Flux estimation analysis systematically characterizes the metabolic shifts of the central metabolism pathway in human cancer.
Glutamine metabolism genes prognostic signature for stomach adenocarcinoma and immune infiltration: potential biomarkers for predicting overall survival.
Mitochondria-Anchoring Self-assembled Nanoparticles for Multi-Path Energy Depletion: A "Nano Bomb" in Chemo-co-Starvation Therapy.
Shutting off the fuel supply to target metabolic vulnerabilities in multiple myeloma.
Astrocytes Differentiated from LRRK2-I1371V Parkinson's-Disease-Induced Pluripotent Stem Cells Exhibit Similar Yield but Cell-Intrinsic Dysfunction in Glutamate Uptake and Metabolism, ATP Generation, and Nrf2-Mediated Glutathione Machinery.
Beggars banquet: Metabolism in the tumor immune microenvironment and cancer therapy.
Glutamine synthetase (GS) knockout (KO) using CRISPR/Cpf1 diversely enhances selection efficiency of CHO cells expressing therapeutic antibodies.
The Interplay between Dysregulated Metabolism and Epigenetics in Cancer.
Increased glucose availability sensitizes pancreatic cancer to chemotherapy.

Mol Biol Rep. 2023 Jun 26.

c-Myc protects hepatocellular carcinoma cell from ferroptosis induced by glutamine deprivation via upregulating GOT1 and Nrf2.

Yuxiang Zhao, Yue Wang, Zeyu Miao, Yan Liu, Qing Yang.

  BACKGROUND: Glutamine metabolism is critical for development of hepatocellular carcinoma (HCC), which makes it a novel promising treatment target. However, clinical evidence suggested glutamine withdrawal therapy does not achieved the desired tumor suppression. Therefore, it is valuable to investigate the survival mechanisms of tumors with glutamine deprivation.METHODS: The HCC cells were cultured in glutamine-free medium or supplemented with glutamine metabolites or ferroptosis inhibitors. The parameters related to ferroptosis and the activity of GSH synthesis-related enzymes of the HCC cells were detected by corresponding kits. The expressions of glutamate oxaloacetate transaminase 1 (GOT1), c-Myc and Nrf2 were detected by western blot and qRT-PCR. The chromatin immunoprecipitation and luciferase reporter assays were performed to investigate the correlation between c-Myc and GOT1. The siRNAs of c-Myc and GOT1 were used to explore their roles in GSH (GSH) synthesis and ferroptosis in vitro and in vivo.
RESULTS: Glutamine deprivation-induced ferroptosis did not completely inhibit HCC cells proliferation. Glutamine deprivation activated the expression of c-Myc, which promoted the transcription of GOT1 and Nrf2, consequently maintaining the GSH synthesis and inhibiting ferroptosis. In addition, combined inhibition of GOT1 with glutamine deprivation could result in better inhibition of HCC in vitro and in vivo.
CONCLUSIONS: In our work, the results indicate that GOT1 induced by c-Myc may play an important role in combating ferroptosis due to glutamine deprivation, making it a significant target in glutamine withdrawal therapy. This study provides a theoretical foundation for the clinical targeted therapy for HCC.

Keywords:  Ferroptosis; GOT1; Glutamine deprivation; Hepatocellular carcinoma; c-Myc

DOI:  https://doi.org/10.1007/s11033-023-08495-1
Cancer Med. 2023 Jun 30.

Glutamine and amino acid metabolism as a prognostic signature and therapeutic target in endometrial cancer.

Lirong Zhai, Xiao Yang, Yuan Cheng, Jianliu Wang.

  INTRODUCTION: Endometrial cancer (EC) is the most common female reproductive system cancer in developed countries with growing incidence and associated mortality, which may be due to the growing prevalence of obesity. Metabolism reprogramming including glucose, amino acid, and lipid remodeling is a hallmark of tumors. Glutamine metabolism has been reported to participate in tumor proliferation and development. This study aimed to develop a glutamine metabolism-related prognostic model for EC and explore potential targets for cancer treatment.METHOD: Transcriptomic data and survival outcome of EC were retrieved from The Cancer Genome Atlas (TCGA). Differentially expressed genes related to glutamine metabolism were recognized and utilized to build a prognostic model by univariate and multivariate Cox regressions. The model was confirmed in the training, testing, and the entire cohort. A nomogram combing prognostic model and clinicopathologic features was established and tested. Moreover, we explored the effect of a key metabolic enzyme, PHGDH, on the biological behavior of EC cell lines and xenograft model.
RESULTS: Five glutamine metabolism-related genes, including PHGDH, OTC, ASRGL1, ASNS, and NR1H4, were involved in prognostic model construction. Kaplan-Meier curve suggested that patients recognized as high risk underwent inferior outcomes. The receiver operating characteristic (ROC) curve showed the model was sufficient to predict survival. Enrichment analysis recognized DNA replication and repair dysfunction in high-risk patients whereas immune relevance analysis revealed low immune scores in the high-risk group. Finally, a nomogram integrating the prognostic model and clinical factors was created and verified. Further, knockdown of PHGDH showed cell growth inhibition, increasing apoptosis, and reduced migration. Promisingly, NCT-503, a PHGDH inhibitor, significantly repressed tumor growth in vivo (p = 0.0002).
CONCLUSION: Our work established and validated a glutamine metabolism-related prognostic model that favorably evaluates the prognosis of EC patients. DNA replication and repair may be the crucial point that linked glutamine metabolism, amino acid metabolism, and EC progression. High-risk patients stratified by the model may not be sufficient for immune therapy. PHGDH might be a crucial target that links serine metabolism, glutamine metabolism as well as EC progression.

Keywords:  DNA repair; PHGDH; amino acid; endometrial cancer; glutamine metabolism; immune response; nomogram; prognosis; serine metabolism

DOI:  https://doi.org/10.1002/cam4.6256
Mol Cancer Res. 2023 Jun 26. pii: MCR-23-0049. [Epub ahead of print]

Mitochondrial uncoupling inhibits reductive carboxylation in cancer cells.

Haowen Jiang, Clifford Jiajun He, Albert M Li, Bo He, Yang Li, Meng-Ning Zhou, Jiangbin Ye.

When the electron transport chain (ETC) function is impaired, cancer cells rely on reductive carboxylation (RC) to convert α-ketoglutarate (αKG) to citrate for macromolecular synthesis, thereby promoting tumor growth. Currently, there is no viable therapy to inhibit RC for cancer treatment. In this study, we demonstrate that the mitochondrial uncoupler treatment effectively inhibits RC in cancer cells. Mitochondrial uncoupler treatment activates the ETC and increases the NAD+/NADH ratio. Using U-13C-glutamine and 1-13C-glutamine tracers, we show that mitochondrial uncoupling accelerates the oxidative TCA cycle and blocks RC under hypoxia, in von Hippel-Lindau (VHL) tumor suppressor-deficient kidney cancer cells, or under anchorage-independent growth condition. Together, these data demonstrate that mitochondrial uncoupling redirects α-KG from RC back to the oxidative TCA cycle, highlighting that the NAD+/NADH ratio is one key switch that determines the metabolic fate of α-KG. Inhibiting RC could be a key mechanism by which mitochondrial uncouplers inhibit tumor growth.

DOI: https://doi.org/10.1158/1541-7786.MCR-23-0049
Oncogene. 2023 Jun 24.

Critical role of antioxidant programs in enzalutamide-resistant prostate cancer.

Eliot B Blatt, Karla Parra, Antje Neeb, Lorenzo Buroni, Denisa Bogdan, Wei Yuan, Yunpeng Gao, Collin Gilbreath, Alec Paschalis, Suzanne Carreira, Ralph J DeBerardinis, Ram S Mani, Johann S de Bono, Ganesh V Raj.

Therapy resistance to second-generation androgen receptor (AR) antagonists, such as enzalutamide, is common in patients with advanced prostate cancer (PCa). To understand the metabolic alterations involved in enzalutamide resistance, we performed metabolomic, transcriptomic, and cistromic analyses of enzalutamide-sensitive and -resistant PCa cells, xenografts, patient-derived organoids, patient-derived explants, and tumors. We noted dramatically higher basal and inducible levels of reactive oxygen species (ROS) in enzalutamide-resistant PCa and castration-resistant PCa (CRPC), in comparison to enzalutamide-sensitive PCa cells or primary therapy-naive tumors respectively. Unbiased metabolomic evaluation identified that glutamine metabolism was consistently upregulated in enzalutamide-resistant PCa cells and CRPC tumors. Stable isotope tracing studies suggest that this enhanced glutamine metabolism drives an antioxidant program that allows these cells to tolerate higher basal levels of ROS. Inhibition of glutamine metabolism with either a small-molecule glutaminase inhibitor or genetic knockout of glutaminase enhanced ROS levels, and blocked the growth of enzalutamide-resistant PCa. The critical role of compensatory antioxidant pathways in maintaining enzalutamide-resistant PCa cells was validated by targeting another antioxidant program driver, ferredoxin 1. Taken together, our data identify a metabolic need to maintain antioxidant programs and a potentially targetable metabolic vulnerability in enzalutamide-resistant PCa.

DOI: https://doi.org/10.1038/s41388-023-02756-w
Front Oncol. 2023 ;13 1117810

Flux estimation analysis systematically characterizes the metabolic shifts of the central metabolism pathway in human cancer.

Grace Yang, Shaoyang Huang, Kevin Hu, Alex Lu, Jonathan Yang, Noah Meroueh, Pengtao Dang, Yijie Wang, Haiqi Zhu, Sha Cao, Chi Zhang.

  Introduction: Glucose and glutamine are major carbon and energy sources that promote the rapid proliferation of cancer cells. Metabolic shifts observed on cell lines or mouse models may not reflect the general metabolic shifts in real human cancer tissue.Method: In this study, we conducted a computational characterization of the flux distribution and variations of the central energy metabolism and key branches in a pan-cancer analysis, including the glycolytic pathway, production of lactate, tricarboxylic acid (TCA) cycle, nucleic acid synthesis, glutaminolysis, glutamate, glutamine, and glutathione metabolism, and amino acid synthesis, in 11 cancer subtypes and nine matched adjacent normal tissue types using TCGA transcriptomics data.
Result: Our analysis confirms the increased influx in glucose uptake and glycolysis and decreased upper part of the TCA cycle, i.e., the Warburg effect, in almost all the analyzed cancer. However, increased lactate production and the second half of the TCA cycle were only seen in certain cancer types. More interestingly, we failed to detect significantly altered glutaminolysis in cancer tissues compared to their adjacent normal tissues. A systems biology model of metabolic shifts through cancer and tissue types is further developed and analyzed. We observed that (1) normal tissues have distinct metabolic phenotypes; (2) cancer types have drastically different metabolic shifts compared to their adjacent normal controls; and (3) the different shifts in tissue-specific metabolic phenotypes result in a converged metabolic phenotype through cancer types and cancer progression.
Discussion: This study strongly suggests the possibility of having a unified framework for studies of cancer-inducing stressors, adaptive metabolic reprogramming, and cancerous behaviors.

Keywords:  TCA cycle; cancer metabolism; flux estimation; glutaminolysis; systems biology

DOI:  https://doi.org/10.3389/fonc.2023.1117810
Front Oncol. 2023 ;13 1201297

Glutamine metabolism genes prognostic signature for stomach adenocarcinoma and immune infiltration: potential biomarkers for predicting overall survival.

Hui Li, Zixuan Wu, Yu Zhang, Xiaohui Lu, Lili Miao.

  Background: Stomach adenocarcinoma (STAD), caused by mutations in stomach cells, is characterized by poor overall survival. Chemotherapy is commonly administered for stomach cancer patients following surgical resection. An imbalance in tumor metabolic pathways is connected to tumor genesis and growth. It has been discovered that glutamine (Gln) metabolism plays a crucial role in cancer. Metabolic reprogramming is associated with clinical prognosis in various cancers. However, the role of glutamine metabolism genes (GlnMgs) in the fight against STAD remains poorly understood.Methods: GlnMgs were determined in STAD samples from the TCGA and GEO datasets. The TCGA and GEO databases provide information on stemness indices (mRNAsi), gene mutations, copy number variations (CNV), tumor mutation burden (TMB), and clinical characteristics. Lasso regression was performed to build the prediction model. The relationship between gene expression and Gln metabolism was investigated using co-expression analysis.
Results: GlnMgs, found to be overexpressed in the high-risk group even in the absence of any symptomatology, demonstrated strong predictive potential for STAD outcomes. GSEA highlighted immunological and tumor-related pathways in the high-risk group. Immune function and m6a gene expression differed significantly between the low- and high-risk groups. AFP, CST6, CGB5, and ELANE may be linked to the oncology process in STAD patients. The prognostic model, CNVs, single nucleotide polymorphism (SNP), and medication sensitivity all revealed a strong link to the gene.
Conclusion: GlnMgs are connected to the genesis and development of STAD. These corresponding prognostic models aid in predicting the prognosis of STAD GlnMgs and immune cell infiltration in the tumor microenvironment (TME) may be possible therapeutic targets in STAD. Furthermore, the glutamine metabolism gene signature presents a credible alternative for predicting STAD outcomes, suggesting that these GlnMgs could open a new field of study for STAD-focused therapy Additional trials are needed to validate the results of the current study.

Keywords:  CNV; GlnMgs; SNP; STAD; drug prediction; immunity; m6A and immune checkpoint

DOI:  https://doi.org/10.3389/fonc.2023.1201297
Int J Pharm. 2023 Jun 24. pii: S0378-5173(23)00600-2. [Epub ahead of print] 123180

Mitochondria-Anchoring Self-assembled Nanoparticles for Multi-Path Energy Depletion: A "Nano Bomb" in Chemo-co-Starvation Therapy.

Kexin Zhang, Jiaxin Zhu, Ruyi Wang, Wanfang Zhu, Zhongtao Zhang, Liangping Gong, Feng Feng, Wenyuan Liu, Lingfei Han, Wei Qu.

  As the main systemic treatment for triple-negative breast cancer (TNBC), the bleak medical prognosis of chemotherapy resulted in impaired life quality by tumor recurrence and metastasis. The feasible cancer starvation therapy could inhibit tumor progression by blocking energy supplements, however, the mono-therapeutic modality showed limited curing efficacy due to heterogeneity and abnormal energy metabolism of TNBC. Thus, the development of a synergistic nano-therapeutic modality involving different anti-tumor mechanisms to simultaneously transport medicines to the organelle where metabolism took place, might remarkably improve curing efficacy, targeting ability, and bio-safety. Herein, the hybrid BLG@TPGS NPs were prepared by doping multi-path energy inhibitors Berberine (BBR) and Lonidamine (LND) as well as the chemotherapeutic agent Gambogic acid (GA). Our research indicated that Nanobomb\mathord{-} BLG@TPGS NPs inherited the mitochondria targeting ability from BBR to accumulate precisely at the "energy factory" mitochondria, and then induce starvation therapy to efficiently eradicated cancer cells by coordinately powered off tumor cells via a "three-prone strategy" to cut off mitochondrial respiration, glycolysis, and glutamine metabolism. The inhibition of tumor proliferation and migration was enlarged by the synergistic combination with chemotherapy. Besides, apoptosis via mitochondria pathway and mitochondria fragmentation supported the hypothesis that NPs eliminated MDA-MB-231 cells by violently attacking MDA-MB-231 cells and especially the mitochondria. In summary, this synergistic chemo-co-starvation nanomedicine proposed an innovative site-specific targeting strategy for improved tumor treatment and decreased toxicity to normal tissues, which provided an option for clinical TNBC-sensitive treatment.

Keywords:  OXPHOS; energy deprivation; glutamine metabolism; glycolysis; mitochondria targeting; synergistic chemo-co-starvation therapy

DOI:  https://doi.org/10.1016/j.ijpharm.2023.123180
Front Oncol. 2023 ;13 1141851

Shutting off the fuel supply to target metabolic vulnerabilities in multiple myeloma.

Priyanka S Rana, Krishna Goparaju, James J Driscoll.

  Pathways that govern cellular bioenergetics are deregulated in tumor cells and represent a hallmark of cancer. Tumor cells have the capacity to reprogram pathways that control nutrient acquisition, anabolism and catabolism to enhance their growth and survival. Tumorigenesis requires the autonomous reprogramming of key metabolic pathways that obtain, generate and produce metabolites from a nutrient-deprived tumor microenvironment to meet the increased bioenergetic demands of cancer cells. Intra- and extracellular factors also have a profound effect on gene expression to drive metabolic pathway reprogramming in not only cancer cells but also surrounding cell types that contribute to anti-tumor immunity. Despite a vast amount of genetic and histologic heterogeneity within and between cancer types, a finite set of pathways are commonly deregulated to support anabolism, catabolism and redox balance. Multiple myeloma (MM) is the second most common hematologic malignancy in adults and remains incurable in the vast majority of patients. Genetic events and the hypoxic bone marrow milieu deregulate glycolysis, glutaminolysis and fatty acid synthesis in MM cells to promote their proliferation, survival, metastasis, drug resistance and evasion of immunosurveillance. Here, we discuss mechanisms that disrupt metabolic pathways in MM cells to support the development of therapeutic resistance and thwart the effects of anti-myeloma immunity. A better understanding of the events that reprogram metabolism in myeloma and immune cells may reveal unforeseen vulnerabilities and advance the rational design of drug cocktails that improve patient survival.

Keywords:  fatty acid synthesis; glycolysis; metabolism; multiple myeloma; oxidative phosphorylation; proteasome inhibitor

DOI:  https://doi.org/10.3389/fonc.2023.1141851
Cells. 2023 06 08. pii: 1592. [Epub ahead of print]12(12):

Astrocytes Differentiated from LRRK2-I1371V Parkinson's-Disease-Induced Pluripotent Stem Cells Exhibit Similar Yield but Cell-Intrinsic Dysfunction in Glutamate Uptake and Metabolism, ATP Generation, and Nrf2-Mediated Glutathione Machinery.

Roon Banerjee, Aishwarya Raj, Chandrakanta Potdar, Pramod Kumar Pal, Ravi Yadav, Nitish Kamble, Vikram Holla, Indrani Datta.

  Owing to the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signaling pathways. It also has several pathological mutant-variants, and their incidences show ethnicity biases and drug-response differences with expression in dopaminergic-neurons and astrocytes. Here, we aimed to assess the cell-intrinsic effect of the LRRK2-I1371V mutant variant, prevalent in East Asian populations, on astrocyte yield and biology, involving Nrf2-mediated glutathione machinery, glutamate uptake and metabolism, and ATP generation in astrocytes derived from LRRK2-I1371V PD patient iPSCs and independently confirmed in LRRK2-I1371V-overexpressed U87 cells. Astrocyte yield (GFAP-immunopositive) was comparable between LRRK2-I1371V and healthy control (HC) populations; however, the astrocytic capability to mitigate oxidative stress in terms of glutathione content was significantly reduced in the mutant astrocytes, along with a reduction in the gene expression of the enzymes involved in glutathione machinery and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Simultaneously, a significant decrease in glutamate uptake was observed in LRRK2-I1371V astrocytes, with lower gene expression of glutamate transporters SLC1A2 and SLC1A3. The reduction in the protein expression of SLC1A2 was also directly confirmed. Enzymes catalyzing the generation of γ glutamyl cysteine (precursor of glutathione) from glutamate and the metabolism of glutamate to enter the Krebs cycle (α-ketoglutaric acid) were impaired, with significantly lower ATP generation in LRRK2-I1371V astrocytes. De novo glutamine synthesis via the conversion of glutamate to glutamine was also affected, indicating glutamate metabolism disorder. Our data demonstrate for the first time that the mutation in the LRRK2-I1371V allele causes significant astrocytic dysfunction with respect to Nrf2-mediated antioxidant machinery, AT -generation, and glutamate metabolism, even with comparable astrocyte yields.

Keywords:  Nrf2-regulated antioxidants; glutamate dehydrogenase; glutamate to glutamine; glutamate transporters; glutamate uptake and metabolism; glutathione; mutations in LRRK2 GTPase domain

DOI:  https://doi.org/10.3390/cells12121592
Cell Metab. 2023 Jun 20. pii: S1550-4131(23)00213-9. [Epub ahead of print]

Beggars banquet: Metabolism in the tumor immune microenvironment and cancer therapy.

Weiping Zou, Douglas R Green.

  Metabolic programming in the tumor microenvironment (TME) alters tumor immunity and immunotherapeutic response in tumor-bearing mice and patients with cancer. Here, we review immune-related functions of core metabolic pathways, key metabolites, and crucial nutrient transporters in the TME, discuss their metabolic, signaling, and epigenetic impact on tumor immunity and immunotherapy, and explore how these insights can be applied to the development of more effective modalities to potentiate the function of T cells and sensitize tumor cell receptivity to immune attack, thereby overcoming therapeutic resistance.

Keywords:  T cell; checkpoint; immunotherapy; metabolism; metabolite; tumor microenvironment

DOI:  https://doi.org/10.1016/j.cmet.2023.06.003
Sci Rep. 2023 06 28. 13(1): 10473

Glutamine synthetase (GS) knockout (KO) using CRISPR/Cpf1 diversely enhances selection efficiency of CHO cells expressing therapeutic antibodies.

Witsanu Srila, Martina Baumann, Markus Riedl, Kuntalee Rangnoi, Nicole Borth, Montarop Yamabhai.

The glutamine synthetase (GS)-based Chinese hamster ovary (CHO) selection system is an attractive approach to efficiently identify suitable clones in the cell line generation process for biologics manufacture, for which GS-knockout (GS-KO) CHO cell lines are commonly used. Since genome analysis indicated that there are two GS genes in CHO cells, deleting only 1 GS gene could potentially result in the activation of other GS genes, consequently reducing the selection efficiency. Therefore, in this study, both GS genes identified on chromosome 5 (GS5) and 1 (GS1) of CHO-S and CHO-K1, were deleted using CRISPR/Cpf1. Both single and double GS-KO CHO-S and K1 showed robust glutamine-dependent growth. Next, the engineered CHO cells were tested for their efficiency of selection of stable producers of two therapeutic antibodies. Analysis of pool cultures and subclones after a single round of 25 µM methionine sulfoxinime (MSX) selection indicated that for CHO-K1 the double GS5,1-KO was more efficient as in the case of a single GS5-KO the GS1 gene was upregulated. In CHO-S, on the other hand, with an autologously lower level of expression of both variants of GS, a single GS5-KO was more robust and already enabled selection of high producers. In conclusion, CRISPR/Cpf1 can be efficiently used to knock out GS genes from CHO cells. The study also indicates that for the generation of host cell lines for efficient selection, the initial characterisation of expression levels of the target gene as well as the identification of potential escape mechanisms is important.

DOI: https://doi.org/10.1038/s41598-023-37288-6
Biomolecules. 2023 06 05. pii: 944. [Epub ahead of print]13(6):

The Interplay between Dysregulated Metabolism and Epigenetics in Cancer.

Mahmoud Adel Bassal.

  Cellular metabolism (or energetics) and epigenetics are tightly coupled cellular processes. It is arguable that of all the described cancer hallmarks, dysregulated cellular energetics and epigenetics are the most tightly coregulated. Cellular metabolic states regulate and drive epigenetic changes while also being capable of influencing, if not driving, epigenetic reprogramming. Conversely, epigenetic changes can drive altered and compensatory metabolic states. Cancer cells meticulously modify and control each of these two linked cellular processes in order to maintain their tumorigenic potential and capacity. This review aims to explore the interplay between these two processes and discuss how each affects the other, driving and enhancing tumorigenic states in certain contexts.

Keywords:  Warburg effect; cancer epigenetics; cancer hallmarks; cancer metabolism

DOI:  https://doi.org/10.3390/biom13060944
Nat Commun. 2023 Jun 28. 14(1): 3823

Increased glucose availability sensitizes pancreatic cancer to chemotherapy.

Ali Vaziri-Gohar, Jonathan J Hue, Ata Abbas, Hallie J Graor, Omid Hajihassani, Mehrdad Zarei, George Titomihelakis, John Feczko, Moeez Rathore, Sylwia Chelstowska, Alexander W Loftus, Rui Wang, Mahsa Zarei, Maryam Goudarzi, Renliang Zhang, Belinda Willard, Li Zhang, Adam Kresak, Joseph E Willis, Gi-Ming Wang, Curtis Tatsuoka, Joseph M Salvino, Ilya Bederman, Henri Brunengraber, Costas A Lyssiotis, Jonathan R Brody, Jordan M Winter.

Pancreatic Ductal Adenocarcinoma (PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, as chemotherapy remains the best available systemic treatment. However, the discovery of safe and available adjuncts to enhance chemotherapeutic efficacy can still improve survival outcomes. We show that a hyperglycemic state substantially enhances the efficacy of conventional single- and multi-agent chemotherapy regimens against PDAC. Molecular analyses of tumors exposed to high glucose levels reveal that the expression of GCLC (glutamate-cysteine ligase catalytic subunit), a key component of glutathione biosynthesis, is diminished, which in turn augments oxidative anti-tumor damage by chemotherapy. Inhibition of GCLC phenocopies the suppressive effect of forced hyperglycemia in mouse models of PDAC, while rescuing this pathway mitigates anti-tumor effects observed with chemotherapy and high glucose.

DOI: https://doi.org/10.1038/s41467-023-38921-8