bims-glucam 2024-05-26 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024–05–26
twenty-one papers selected by
Sreeparna Banerjee, Middle East Technical University

AGC1-mediated Metabolic Reprogramming and Autophagy Sustain Survival of Hepatocellular Carcinoma Cells under Glutamine Deprivation.
Immunological Aspects of Cancer Cell Metabolism.
Targeting glutamine metabolism improves sarcoma response to radiation therapy in vivo.
Metabolic Roles of HIF1, c-Myc, and p53 in Glioma Cells.
Enzymatic depletion of circulating glutamine is immunosuppressive in cancers.
Engineering the Signal Resolution of a Paper-Based Cell-Free Glutamine Biosensor with Genetic Engineering, Metabolic Engineering, and Process Optimization.
Dual Starvations Induce Pyroptosis for Orthotopic Pancreatic Cancer Therapy through Simultaneous Deprivation of Glucose and Glutamine.
Role of ammonia and glutamine in the pathogenesis and progression of metabolic dysfunction-associated steatotic liver disease: A systematic review.
AMPK-a key factor in crosstalk between tumor cell energy metabolism and immune microenvironment?
The OGT-c-Myc-PDK2 axis rewires the TCA cycle and promotes colorectal tumor growth.
Mitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC.
Targeting lipid reprogramming in the tumor microenvironment by traditional Chinese medicines as a potential cancer treatment.
Glutathione Depletion and Stalwart Anticancer Activity of Metallotherapeutics Inducing Programmed Cell Death: Opening a New Window for Cancer Therapy.
The interplay between metabolic adaptations and diet in cancer immunotherapy.
Delving into the Metabolism of Sézary Cells: A Brief Review.
Mechanism of cytochrome P450s mediated interference with glutathione and amino acid metabolisms from halogenated PAHs exposure.
Subcellular distribution and Nrf2/Keap1-interacting properties of Glutathione S-transferase P in hepatocellular carcinoma.
Black raspberry-mediated metabolic changes in patients with familial adenomatous polyposis associated with rectal polyp regression.
Exploring free amino acid profiles in Crimean-Congo hemorrhagic fever patients: Implications for disease progression.
Cellular signaling in glioblastoma: A molecular and clinical perspective.
Bag1 protein loss sensitizes mouse embryonic fibroblasts to glutathione depletion.

Cell Biochem Biophys. 2024 May 24.

AGC1-mediated Metabolic Reprogramming and Autophagy Sustain Survival of Hepatocellular Carcinoma Cells under Glutamine Deprivation.

Yan Liu, Zeyu Miao, Qing Yang.

  The dependence of hepatocellular carcinoma (HCC) cells on glutamine suggests the feasibility of targeting glutamine metabolism for therapy. However, drugs inhibiting glutamine uptake and breakdown have not shown promising outcomes. Therefore, investigating the mechanism of glutamine metabolism reprogramming in HCC cells is crucial. We used bioinformatics approaches to investigate the metabolic flux of glutamine in HCC cells and validated it using qRT-PCR and western blotting. HCC cells were cultured in glutamine-deprived medium, and changes in glutamate and ATP levels were monitored. Western blotting was employed to assess the expression of AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) and autophagy-related proteins. The impact of Solute carrier family 25 member 12 (AGC1) on HCC cell proliferation was studied using CCK-8 and colony formation assays. Furthermore, the effects of AGC1 knockdown via siRNA on metabolic reprogramming and energy supply during glutamine deprivation in HCC were explored. During glutamine deprivation, HCC cells sustain cytosolic asparagine synthesis and ATP production through AGC1. Low ATP levels activate AMPK and inhibit mTOR activation, inducing autophagy to rescue HCC cell survival. Knockdown of AGC1 inhibits mitochondrial aspartate output and continuously activates autophagy, rendering HCC cells more sensitive to glutamine deprivation. AGC1 serves as a critical node in the reprogramming of glutamine metabolism and energy supply in HCC cells. This study provides theoretical support for overcoming resistance to drugs targeting glutamine metabolism.

Keywords:  AGC1; Autophagy; Glutamine deprivation; Hepatocellular carcinoma; Metabolic reprogramming

DOI:  https://doi.org/10.1007/s12013-024-01311-y
Int J Mol Sci. 2024 May 13. pii: 5288. [Epub ahead of print]25(10):

Immunological Aspects of Cancer Cell Metabolism.

Sisca Ucche, Yoshihiro Hayakawa.

  Cancer cells adeptly manipulate their metabolic processes to evade immune detection, a phenomenon intensifying the complexity of cancer progression and therapy. This review delves into the critical role of cancer cell metabolism in the immune-editing landscape, highlighting how metabolic reprogramming facilitates tumor cells to thrive despite immune surveillance pressures. We explore the dynamic interactions within the tumor microenvironment (TME), where cancer cells not only accelerate their glucose and amino acid metabolism but also induce an immunosuppressive state that hampers effective immune response. Recent findings underscore the metabolic competition between tumor and immune cells, particularly focusing on how this interaction influences the efficacy of emerging immunotherapies. By integrating cutting-edge research on the metabolic pathways of cancer cells, such as the Warburg effect and glutamine addiction, we shed light on potential therapeutic targets. The review proposes that disrupting these metabolic pathways could enhance the response to immunotherapy, offering a dual-pronged strategy to combat tumor growth and immune evasion.

Keywords:  cancer; immune escape; immune surveillance; metabolism; progression

DOI:  https://doi.org/10.3390/ijms25105288
Commun Biol. 2024 May 20. 7(1): 608

Targeting glutamine metabolism improves sarcoma response to radiation therapy in vivo.

Rutulkumar Patel, Daniel E Cooper, Kushal T Kadakia, Annamarie Allen, Likun Duan, Lixia Luo, Nerissa T Williams, Xiaojing Liu, Jason W Locasale, David G Kirsch.

Diverse tumor metabolic phenotypes are influenced by the environment and genetic lesions. Whether these phenotypes extend to rhabdomyosarcoma (RMS) and how they might be leveraged to design new therapeutic approaches remains an open question. Thus, we utilized a Pax7Cre-ER-T2/+; NrasLSL-G12D/+; p53fl/fl (P7NP) murine model of sarcoma with mutations that most frequently occur in human embryonal RMS. To study metabolism, we infuse 13C-labeled glucose or glutamine into mice with sarcomas and show that sarcomas consume more glucose and glutamine than healthy muscle tissue. However, we reveal a marked shift from glucose consumption to glutamine metabolism after radiation therapy (RT). In addition, we show that inhibiting glutamine, either through genetic deletion of glutaminase (Gls1) or through pharmacological inhibition of glutaminase, leads to significant radiosensitization in vivo. This causes a significant increase in overall survival for mice with Gls1-deficient compared to Gls1-proficient sarcomas. Finally, Gls1-deficient sarcomas post-RT elevate levels of proteins involved in natural killer cell and interferon alpha/gamma responses, suggesting a possible role of innate immunity in the radiosensitization of Gls1-deficient sarcomas. Thus, our results indicate that glutamine contributes to radiation response in a mouse model of RMS.

DOI: https://doi.org/10.1038/s42003-024-06262-x
Metabolites. 2024 Apr 25. pii: 249. [Epub ahead of print]14(5):

Metabolic Roles of HIF1, c-Myc, and p53 in Glioma Cells.

Cristina Trejo-Solís, Rosa Angélica Castillo-Rodríguez, Norma Serrano-García, Daniela Silva-Adaya, Salvador Vargas-Cruz, Elda Georgina Chávez-Cortéz, Juan Carlos Gallardo-Pérez, Sergio Zavala-Vega, Arturo Cruz-Salgado, Roxana Magaña-Maldonado.

  The metabolic reprogramming that promotes tumorigenesis in glioblastoma is induced by dynamic alterations in the hypoxic tumor microenvironment, as well as in transcriptional and signaling networks, which result in changes in global genetic expression. The signaling pathways PI3K/AKT/mTOR and RAS/RAF/MEK/ERK stimulate cell metabolism, either directly or indirectly, by modulating the transcriptional factors p53, HIF1, and c-Myc. The overexpression of HIF1 and c-Myc, master regulators of cellular metabolism, is a key contributor to the synthesis of bioenergetic molecules that mediate glioma cell transformation, proliferation, survival, migration, and invasion by modifying the transcription levels of key gene groups involved in metabolism. Meanwhile, the tumor-suppressing protein p53, which negatively regulates HIF1 and c-Myc, is often lost in glioblastoma. Alterations in this triad of transcriptional factors induce a metabolic shift in glioma cells that allows them to adapt and survive changes such as mutations, hypoxia, acidosis, the presence of reactive oxygen species, and nutrient deprivation, by modulating the activity and expression of signaling molecules, enzymes, metabolites, transporters, and regulators involved in glycolysis and glutamine metabolism, the pentose phosphate cycle, the tricarboxylic acid cycle, and oxidative phosphorylation, as well as the synthesis and degradation of fatty acids and nucleic acids. This review summarizes our current knowledge on the role of HIF1, c-Myc, and p53 in the genic regulatory network for metabolism in glioma cells, as well as potential therapeutic inhibitors of these factors.

Keywords:  AKT; HIF1; c-Myc; glioma; metabolism; p53; therapeutic targets

DOI:  https://doi.org/10.3390/metabo14050249
iScience. 2024 Jun 21. 27(6): 109817

Enzymatic depletion of circulating glutamine is immunosuppressive in cancers.

Monish Kumar, Ankita Leekha, Suman Nandy, Rohan Kulkarni, Melisa Martinez-Paniagua, K M Samiur Rahman Sefat, Richard C Willson, Navin Varadarajan.

  Although glutamine addiction in cancer cells is extensively reported, there is controversy on the impact of glutamine metabolism on the immune cells within the tumor microenvironment (TME). To address the role of extracellular glutamine, we enzymatically depleted circulating glutamine using PEGylated Helicobacter pylori gamma-glutamyl transferase (PEG-GGT) in syngeneic mouse models of breast and colon cancers. PEG-GGT treatment inhibits growth of cancer cells in vitro, but in vivo it increases myeloid-derived suppressor cells (MDSCs) and has no significant impact on tumor growth. By deriving a glutamine depletion signature, we analyze diverse human cancers within the TCGA and illustrate that glutamine depletion is not associated with favorable clinical outcomes and correlates with accumulation of MDSC. Broadly, our results help clarify the integrated impact of glutamine depletion within the TME and advance PEG-GGT as an enzymatic tool for the systemic and selective depletion (no asparaginase activity) of circulating glutamine in live animals.

Keywords:  Cancer; Immunity; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2024.109817
Sensors (Basel). 2024 May 12. pii: 3073. [Epub ahead of print]24(10):

Engineering the Signal Resolution of a Paper-Based Cell-Free Glutamine Biosensor with Genetic Engineering, Metabolic Engineering, and Process Optimization.

Tyler J Free, Joseph P Talley, Chad D Hyer, Catherine J Miller, Joel S Griffitts, Bradley C Bundy.

  Specialized cancer treatments have the potential to exploit glutamine dependence to increase patient survival rates. Glutamine diagnostics capable of tracking a patient's response to treatment would enable a personalized treatment dosage to optimize the tradeoff between treatment success and dangerous side effects. Current clinical glutamine testing requires sophisticated and expensive lab-based tests, which are not broadly available on a frequent, individualized basis. To address the need for a low-cost, portable glutamine diagnostic, this work engineers a cell-free glutamine biosensor to overcome assay background and signal-to-noise limitations evident in previously reported studies. The findings from this work culminate in the development of a shelf-stable, paper-based, colorimetric glutamine test with a high signal strength and a high signal-to-background ratio for dramatically improved signal resolution. While the engineered glutamine test is important progress towards improving the management of cancer and other health conditions, this work also expands the assay development field of the promising cell-free biosensing platform, which can facilitate the low-cost detection of a broad variety of target molecules with high clinical value.

Keywords:  biosensor; cancer; cell-free protein synthesis (CFPS); glutamine

DOI:  https://doi.org/10.3390/s24103073
J Am Chem Soc. 2024 May 22.

Dual Starvations Induce Pyroptosis for Orthotopic Pancreatic Cancer Therapy through Simultaneous Deprivation of Glucose and Glutamine.

Xinlong Wang, Binbin Ding, Wei Liu, Lishuang Qi, Jiating Li, Xin Zheng, Yiqin Song, Qiyuan Li, Jiawen Wu, Meng Zhang, Hua Chen, Yongwei Wang, Yilong Li, Bei Sun, Ping'an Ma.

Pancreatic cancer is a highly fatal disease, and existing treatment methods are ineffective, so it is urgent to develop new effective treatment strategies. The high dependence of pancreatic cancer cells on glucose and glutamine suggests that disrupting this dependency could serve as an alternative strategy for pancreatic cancer therapy. We identified the vital genes glucose transporter 1 (GLUT1) and alanine-serine-cysteine transporter 2 (ASCT2) through bioinformatics analysis, which regulate glucose and glutamine metabolism in pancreatic cancer, respectively. Human serum albumin nanoparticles (HSA NPs) for delivery of GLUT1 and ASCT2 inhibitors, BAY-876/V-9302@HSA NPs, were prepared by a self-assembly process. This nanodrug inhibits glucose and glutamine uptake of pancreatic cancer cells through the released BAY-876 and V-9302, leading to nutrition deprivation and oxidative stress. The inhibition of glutamine leads to the inhibition of the synthesis of the glutathione, which further aggravates oxidative stress. Both of them lead to a significant increase in reactive oxygen species, activating caspase 1 and GSDMD and finally inducing pyroptosis. This study provides a new effective strategy for orthotopic pancreatic cancer treatment by dual starvation-induced pyroptosis. The study for screening metabolic targets using bioinformatics analysis followed by constructing nanodrugs loaded with inhibitors will inspire future targeted metabolic therapy for pancreatic cancer.

DOI: https://doi.org/10.1021/jacs.4c03478
J Gastroenterol Hepatol. 2024 May 19.

Role of ammonia and glutamine in the pathogenesis and progression of metabolic dysfunction-associated steatotic liver disease: A systematic review.

Basile Njei, Yazan A Al-Ajlouni, Prince Ameyaw, Lea-Pearl Njei, Sarpong Boateng.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 30% of the global population, with a significant risk of advancing to liver cirrhosis and hepatocellular carcinoma. The roles of ammonia and glutamine in MASLD's pathogenesis are increasingly recognized, prompting this systematic review. This systematic review was conducted through a meticulous search of literature on December 21, 2023, across five major databases, focusing on studies that addressed the relationship between ammonia or glutamine and MASLD. The quality of the included studies was evaluated using CASP checklists. This study is officially registered in the PROSPERO database (CRD42023495619) and was conducted without external funding or sponsorship. Following PRISMA guidelines, 13 studies were included in this review. The studies were conducted globally, with varying sample sizes and study designs. The appraisal indicated a mainly low bias, confirming the reliability of the evidence. Glutamine's involvement in MASLD emerged as multifaceted, with its metabolic role being critical for liver function and disease progression. Variable expressions of glutamine synthetase and glutaminase enzymes highlight metabolic complexity whereas ammonia's impact through urea cycle dysfunction suggests avenues for therapeutic intervention. However, human clinical trials are lacking. This review emphasizes the necessity of glutamine and ammonia in understanding MASLD and identifies potential therapeutic targets. The current evidence, while robust, points to the need for human studies to corroborate preclinical findings. A personalized approach to treatment, informed by metabolic differences in MASLD patients, is advocated, alongside future large-scale clinical trials for a deeper exploration into these metabolic pathways.

Keywords:  Ammonia metabolism; Glutamine pathophysiology; Liver disease progression; Metabolic dysfunction‐associated steatohepatitis (MASLD); Systematic review

DOI:  https://doi.org/10.1111/jgh.16603
Cell Death Discov. 2024 May 18. 10(1): 237

AMPK-a key factor in crosstalk between tumor cell energy metabolism and immune microenvironment?

Na Wang, Bofang Wang, Ewetse Paul Maswikiti, Yang Yu, Kewei Song, Chenhui Ma, Xiaowen Han, Huanhuan Ma, Xiaobo Deng, Rong Yu, Hao Chen.

Immunotherapy has now garnered significant attention as an essential component in cancer therapy during this new era. However, due to immune tolerance, immunosuppressive environment, tumor heterogeneity, immune escape, and other factors, the efficacy of tumor immunotherapy has been limited with its application to very small population size. Energy metabolism not only affects tumor progression but also plays a crucial role in immune escape. Tumor cells are more metabolically active and need more energy and nutrients to maintain their growth, which causes the surrounding immune cells to lack glucose, oxygen, and other nutrients, with the result of decreased immune cell activity and increased immunosuppressive cells. On the other hand, immune cells need to utilize multiple metabolic pathways, for instance, cellular respiration, and oxidative phosphorylation pathways to maintain their activity and normal function. Studies have shown that there is a significant difference in the energy expenditure of immune cells in the resting and activated states. Notably, competitive uptake of glucose is the main cause of impaired T cell function. Conversely, glutamine competition often affects the activation of most immune cells and the transformation of CD4+T cells into inflammatory subtypes. Excessive metabolite lactate often impairs the function of NK cells. Furthermore, the metabolite PGE2 also often inhibits the immune response by inhibiting Th1 differentiation, B cell function, and T cell activation. Additionally, the transformation of tumor-suppressive M1 macrophages into cancer-promoting M2 macrophages is influenced by energy metabolism. Therefore, energy metabolism is a vital factor and component involved in the reconstruction of the tumor immune microenvironment. Noteworthy and vital is that not only does the metabolic program of tumor cells affect the antigen presentation and recognition of immune cells, but also the metabolic program of immune cells affects their own functions, ultimately leading to changes in tumor immune function. Metabolic intervention can not only improve the response of immune cells to tumors, but also increase the immunogenicity of tumors, thereby expanding the population who benefit from immunotherapy. Consequently, identifying metabolic crosstalk molecules that link tumor energy metabolism and immune microenvironment would be a promising anti-tumor immune strategy. AMPK (AMP-activated protein kinase) is a ubiquitous serine/threonine kinase in eukaryotes, serving as the central regulator of metabolic pathways. The sequential activation of AMPK and its associated signaling cascades profoundly impacts the dynamic alterations in tumor cell bioenergetics. By modulating energy metabolism and inflammatory responses, AMPK exerts significant influence on tumor cell development, while also playing a pivotal role in tumor immunotherapy by regulating immune cell activity and function. Furthermore, AMPK-mediated inflammatory response facilitates the recruitment of immune cells to the tumor microenvironment (TIME), thereby impeding tumorigenesis, progression, and metastasis. AMPK, as the link between cell energy homeostasis, tumor bioenergetics, and anti-tumor immunity, will have a significant impact on the treatment and management of oncology patients. That being summarized, the main objective of this review is to pinpoint the efficacy of tumor immunotherapy by regulating the energy metabolism of the tumor immune microenvironment and to provide guidance for the development of new immunotherapy strategies.

DOI: https://doi.org/10.1038/s41420-024-02011-5
Cell Death Differ. 2024 May 22.

The OGT-c-Myc-PDK2 axis rewires the TCA cycle and promotes colorectal tumor growth.

Huijuan Wang, Jie Sun, Haofan Sun, Yifei Wang, Bingyi Lin, Liming Wu, Weijie Qin, Qiang Zhu, Wen Yi.

Deregulated glucose metabolism termed the "Warburg effect" is a fundamental feature of cancers, including the colorectal cancer. This is typically characterized with an increased rate of glycolysis, and a concomitant reduced rate of the tricarboxylic acid (TCA) cycle metabolism as compared to the normal cells. How the TCA cycle is manipulated in cancer cells remains unknown. Here, we show that O-linked N-acetylglucosamine (O-GlcNAc) regulates the TCA cycle in colorectal cancer cells. Depletion of OGT, the sole transferase of O-GlcNAc, significantly increases the TCA cycle metabolism in colorectal cancer cells. Mechanistically, OGT-catalyzed O-GlcNAc modification of c-Myc at serine 415 (S415) increases c-Myc stability, which transcriptionally upregulates the expression of pyruvate dehydrogenase kinase 2 (PDK2). PDK2 phosphorylates pyruvate dehydrogenase (PDH) to inhibit the activity of mitochondrial pyruvate dehydrogenase complex, which reduces mitochondrial pyruvate metabolism, suppresses reactive oxygen species production, and promotes xenograft tumor growth. Furthermore, c-Myc S415 glycosylation levels positively correlate with PDK2 expression levels in clinical colorectal tumor tissues. This study highlights the OGT-c-Myc-PDK2 axis as a key mechanism linking oncoprotein activation with deregulated glucose metabolism in colorectal cancer.

DOI: https://doi.org/10.1038/s41418-024-01315-4
Nat Commun. 2024 May 18. 15(1): 4244

Mitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC.

Nathan P Ward, Sang Jun Yoon, Tyce Flynn, Amanda M Sherwood, Maddison A Olley, Juliana Madej, Gina M DeNicola.

Cysteine metabolism occurs across cellular compartments to support diverse biological functions and prevent the induction of ferroptosis. Though the disruption of cytosolic cysteine metabolism is implicated in this form of cell death, it is unknown whether the substantial cysteine metabolism resident within the mitochondria is similarly pertinent to ferroptosis. Here, we show that despite the rapid depletion of intracellular cysteine upon loss of extracellular cystine, cysteine-dependent synthesis of Fe-S clusters persists in the mitochondria of lung cancer cells. This promotes a retention of respiratory function and a maintenance of the mitochondrial redox state. Under these limiting conditions, we find that glutathione catabolism by CHAC1 supports the mitochondrial cysteine pool to sustain the function of the Fe-S proteins critical to oxidative metabolism. We find that disrupting Fe-S cluster synthesis under cysteine restriction protects against the induction of ferroptosis, suggesting that the preservation of mitochondrial function is antagonistic to survival under starved conditions. Overall, our findings implicate mitochondrial cysteine metabolism in the induction of ferroptosis and reveal a mechanism of mitochondrial resilience in response to nutrient stress.

DOI: https://doi.org/10.1038/s41467-024-48695-2
Heliyon. 2024 May 15. 10(9): e30807

Targeting lipid reprogramming in the tumor microenvironment by traditional Chinese medicines as a potential cancer treatment.

Qian Zuo, Yingchao Wu, Yuyu Hu, Cui Shao, Yuqi Liang, Liushan Chen, Qianqian Guo, Ping Huang, Qianjun Chen.

  In the last ten years, there has been a notable rise in the study of metabolic abnormalities in cancer cells. However, compared to glucose or glutamine metabolism, less attention has been paid to the importance of lipid metabolism in tumorigenesis. Recent developments in lipidomics technologies have allowed for detailed analysis of lipid profiles within cancer cells and other cellular players present within the tumor microenvironment (TME). Traditional Chinese medicine (TCM) and its bioactive components have a long history of use in cancer treatments and are also being studied for their potential role in regulating metabolic reprogramming within TME. This review focuses on four core abnormalities altered by lipid reprogramming in cancer cells: de novo synthesis and exogenous uptake of fatty acids (FAs), upregulated fatty acid oxidation (FAO), cholesterol accumulation, which offer benefits for tumor growth and metastasis. The review also discusses how altered lipid metabolism impacts infiltrating immune cell function and phenotype as these interactions between cancer-stromal become more pronounced during tumor progression. Finally, recent literature is highlighted regarding how cancer cells can be metabolically reprogrammed by specific Chinese herbal components with potential therapeutic benefits related to lipid metabolic and signaling pathways.

Keywords:  Fatty acids; Lipid droplet; Lipid reprogramming; Traditional Chinese medicines; Tumor microenvironment; de novo lipogenesis

DOI:  https://doi.org/10.1016/j.heliyon.2024.e30807
ACS Omega. 2024 May 14. 9(19): 20670-20701

Glutathione Depletion and Stalwart Anticancer Activity of Metallotherapeutics Inducing Programmed Cell Death: Opening a New Window for Cancer Therapy.

Nilmadhab Roy, Priyankar Paira.

The cellular defense system against exogenous substances makes therapeutics inefficient as intracellular glutathione (GSH) exhibits an astounding antioxidant activity in scavenging reactive oxygen species (ROS) or reactive nitrogen species (RNS) or other free radicals produced by the therapeutics. In the cancer cell microenvironment, the intracellular GSH level becomes exceptionally high to fight against oxidative stress created by the production of ROS/RNS or any free radicals, which are the byproducts of intracellular redox reactions or cellular respiration processes. Thus, in order to maintain redox homeostasis for survival of cancer cells and their rapid proliferation, the GSH level starts to escalate. In this circumstance, the administration of anticancer therapeutics is in vain, as the elevated GSH level reduces their potential by reduction or by scavenging the ROS/RNS they produce. Therefore, in order to augment the therapeutic potential of anticancer agents against elevated GSH condition, the GSH level must be depleted by hook or by crook. Hence, this Review aims to compile precisely the role of GSH in cancer cells, the importance of its depletion for cancer therapy and examples of anticancer activity of a few selected metal complexes which are able to trigger cancer cell death by depleting the GSH level.

DOI: https://doi.org/10.1021/acsomega.3c08890
Clin Cancer Res. 2024 May 21.

The interplay between metabolic adaptations and diet in cancer immunotherapy.

Lena Espelage, Natalie Wagner, Jan Malte Placke, Selma Ugurel, Alpaslan Tasdogan.

Over the past decade, cancer immunotherapy has significantly advanced through the introduction of immune checkpoint inhibitors, and the augmentation of adoptive cell transfer to enhance the innate cancer defense mechanisms. Despite these remarkable achievements, some cancers exhibit resistance to immunotherapy, with limited patient responsiveness and development of therapy resistance. Metabolic adaptations in both immune cells and cancer cells have emerged as central contributors to immunotherapy resistance. In the last few years, new insights emphasized the critical role of cancer and immune cell metabolism in animal models and patients. During therapy, immune cells undergo important metabolic shifts crucial for their acquired effector function against cancer cells. However, cancer cell metabolic rewiring and nutrient competition within tumor microenvironment (TME) alters many immune functions, affecting their fitness, polarization, recruitment, and survival. These interactions have initiated the development of novel therapies targeting tumor cell metabolism and favoring anti-tumor immunity within the TME. Furthermore, there has been increasing interest in comprehending how diet impacts the response to immunotherapy, given the demonstrated immunomodulatory and anti-tumor activity of various nutrients. In conclusion, recent advances in preclinical and clinical studies have highlighted the capacity of immune-based cancer therapies. Therefore, further exploration into the metabolic requirements of immune cells within the TME holds significant promise for the development of innovative therapeutical approaches that can effectively combat cancer in patients.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-3468
Genes (Basel). 2024 May 17. pii: 635. [Epub ahead of print]15(5):

Delving into the Metabolism of Sézary Cells: A Brief Review.

Carel Cherfan, Alain Chebly, Hamid Reza Rezvani, Marie Beylot-Barry, Edith Chevret.

  Primary cutaneous lymphomas (PCLs) are a heterogeneous group of lymphoproliferative disorders caused by the accumulation of neoplastic T or B lymphocytes in the skin. Sézary syndrome (SS) is an aggressive and rare form of cutaneous T cell lymphoma (CTCL) characterized by an erythroderma and the presence of atypical cerebriform T cells named Sézary cells in skin and blood. Most of the available treatments for SS are not curative, which means there is an urgent need for the development of novel efficient therapies. Recently, targeting cancer metabolism has emerged as a promising strategy for cancer therapy. This is due to the accumulating evidence that metabolic reprogramming highly contributes to tumor progression. Genes play a pivotal role in regulating metabolic processes, and alterations in these genes can disrupt the delicate balance of metabolic pathways, potentially contributing to cancer development. In this review, we discuss the importance of targeting energy metabolism in tumors and the currently available data on the metabolism of Sézary cells, paving the way for potential new therapeutic approaches aiming to improve clinical outcomes for patients suffering from SS.

Keywords:  Sézary syndrome; cancer; cutaneous T cell lymphomas; metabolism; therapy

DOI:  https://doi.org/10.3390/genes15050635
J Hazard Mater. 2024 May 11. pii: S0304-3894(24)01168-3. [Epub ahead of print]473 134589

Mechanism of cytochrome P450s mediated interference with glutathione and amino acid metabolisms from halogenated PAHs exposure.

Jiaying Ma, Hang Yu, Guiying Li, Taicheng An.

  Epidemiological evidence indicates that exposure to halogenated polycyclic aromatic hydrocarbons (HPAHs) is associated with many adverse effects. However, the mechanisms of metabolic disorder of HPAHs remains limited. Herein, effects of pyrene (Pyr), and its halogenated derivatives (1-chloropyrene (1-Cl-Pyr), 1-bromopyrene (1-Br-Pyr)) on endogenous metabolic pathways were investigated, in human hepatoma (HepG2) and HepG2-derived cell lines expressing various human cytochrome P450s (CYPs). Non-targeted metabolomics results suggested that 1-Br-Pyr and Pyr exposure (625 nM) induced disruption in glutathione and riboflavin metabolism which associated with redox imbalance, through abnormal accumulation of oxidized glutathione, mediated by bioactivation of CYP2E1. Conversely, CYP2C9-mediated 1-Cl-Pyr significantly interfered with glutathione metabolism intermediates, including glycine, L-glutamic acid and pyroglutamic acid. Notably, CYP1A1-mediated Pyr-induced perturbation of amino acid metabolism which associated with nutrition and glycolipid metabolism, resulting in significant upregulation of most amino acids, whereas halogenated derivatives mediated by CYP1A2 substantially downregulated amino acids. In conclusion, this study suggested that Pyr and its halogenated derivatives exert potent effects on endogenous metabolism disruption under the action of various exogenous metabolic enzymes (CYPs). Thus, new evidence was provided to toxicological mechanisms of HPAHs, and reveals potential health risks of HPAHs in inducing diseases caused by redox and amino acid imbalances.

Keywords:  1-Br-Pyr; 1-Cl-Pyr; Cytochrome P450s; Metabolic activation; Metabolomics

DOI:  https://doi.org/10.1016/j.jhazmat.2024.134589
Arch Biochem Biophys. 2024 May 22. pii: S0003-9861(24)00164-4. [Epub ahead of print] 110043

Subcellular distribution and Nrf2/Keap1-interacting properties of Glutathione S-transferase P in hepatocellular carcinoma.

Desirée Bartolini, Anna Maria Stabile, Anna Migni, Fabio Gurrado, Gessica Lioci, Francesca De Franco, Martina Mandarano, Gianluca Svegliati-Baroni, Manlio Di Cristina, Guido Bellezza, Mario Rende, Francesco Galli.

  The oncogene and phase 2 detoxification enzyme glutathione S-transferase P (GSTP) is a GSH-dependent chaperone of signal transduction and transcriptional proteins with key role in liver carcinogenesis. In this study, we explored this role of GSTP in hepatocellular carcinoma (HCC) investigating the possible interaction of this protein with one of its transcription factor and metronome of cancer cell redox, namely the nuclear factor erythroid 2-related factor 2 (Nrf2). Expression, cellular distribution, and function as glutathionylation factor of GSTP1-1 isoform were investigated in the mouse model of N-nitrosodiethylamine (DEN)-induced HCC and in vitro in human HCC cell lines. The GSTP-Nrf2/Keap1 physical and functional interaction was investigated by immunoprecipitation and gene manipulation experiments. GSTP protein increased its liver expression, enzymatic activity and nuclear levels during DEN-induced tumor development in mice; protein glutathionylation (PSSG) was increased in the tumor masses. Higher levels and a preferential nuclear localization of GSTP protein were also observed in HepG2 and Huh-7 hepatocarcinoma cells compared to HepaRG non-cancerous cells, along with increased basal and Ebselen-stimulated levels of free GSH and PSSG. GSTP activity inhibition with the GSH analogue EZT induced apoptotic cell death in HCC cells. Hepatic Nrf2 and c-Jun, two transcription factors involved in GSTP expression and GSH biosynthesis, were induced in DEN-HCC compared to control animals; the Nrf2 inhibitory proteins Keap1 and β-TrCP also increased and GSTP co-immunoprecipitated with both Nrf2 and Keap1. Nrf2 nuclear translocation and β-TrCP expression also increased in HCC cells, whereas the GSTP transfection in HepaRG cells induced Nrf2 transcriptional activation. In conclusion, GSTP expression and subcellular distribution can contribute to the GSH-dependent redox reprogramming of HCC cells directly influencing the Nrf2/Keap1 system.

Keywords:  DEN; GSTP; HCC; N-nitrosodiethylamine; Nrf2; glutathione; hepatocellular carcinoma; liver cancer

DOI:  https://doi.org/10.1016/j.abb.2024.110043
Food Front. 2024 Mar;5(2): 259-266

Black raspberry-mediated metabolic changes in patients with familial adenomatous polyposis associated with rectal polyp regression.

Yi-Wen Huang, Hui-Zhi Chen, Ben Niu, Weijie Wu, Haiyan Gao, Jianhua Yu, Li-Shu Wang.

  Familial adenomatous polyposis (FAP) patients face an almost certain 100% risk of developing colorectal cancer, necessitating prophylactic colectomy to prevent disease progression. A crucial goal is to hinder this progression. In a recent clinical trial involving 14 FAP patients, half received 60 g of black raspberry (BRB) powder orally and BRB suppositories at bedtime, while the other half received only BRB suppositories at bedtime over 9 months. This intervention led to a notable reduction in rectal polyps for 11 patients, although 3 showed no response. In this study, we delved into the metabolic changes induced by BRBs in the same patient cohort. Employing mass spectrometry-based non-targeted metabolomics, we analyzed pre- and post-BRB urinary and plasma samples from the 11 responders. The results showed significant alterations in 23 urinary and 6 plasma metabolites, influencing various pathways including polyamine, glutathione metabolism, the tricarboxylic acid cycle, inositol metabolism, and benzoate production. BRBs notably elevated levels of several metabolites associated with these pathways, suggesting a potential mechanism through which BRBs facilitate rectal polyp regression in FAP patients by modulating multiple metabolic pathways. Notably, metabolites derived from BRB polyphenols were significantly increased post-BRB intervention, emphasizing the potential therapeutic value of BRBs in FAP management.

Keywords:  Black raspberries; TCA cycle; benzoates; familial adenomatous polyposis; glutathione metabolism; inositol metabolism; metabolomics; polyamine pathway

DOI:  https://doi.org/10.1002/fft2.323
J Med Virol. 2024 May;96(5): e29637

Exploring free amino acid profiles in Crimean-Congo hemorrhagic fever patients: Implications for disease progression.

Seyit Ali Büyüktuna, Serra İlayda Yerlitaş, Gözde Ertük Zararsız, Kübra Doğan, Demet Kablan, Gökhan Bağcı, Selda Özer, Cihad Baysal, Yasemin Çakır, Ahu Cephe, Necla Koçhan, Gökmen Zararız, Halef Okan Doğan.

  This study investigated the intricate interplay between Crimean-Congo hemorrhagic fever virus infection and alterations in amino acid metabolism. The primary aim is to elucidate the impact of Crimean-Congo hemorrhagic fever (CCHF) on specific amino acid concentrations and identify potential metabolic markers associated with viral infection. One hundred ninety individuals participated in this study, comprising 115 CCHF patients, 30 CCHF negative patients, and 45 healthy controls. Liquid chromatography-tandem mass spectrometry techniques were employed to quantify amino acid concentrations. The amino acid metabolic profiles in CCHF patients exhibit substantial distinctions from those in the control group. Patients highlight distinct metabolic reprogramming, notably characterized by arginine, histidine, taurine, glutamic acid, and glutamine metabolism shifts. These changes have been associated with the underlying molecular mechanisms of the disease. Exploring novel therapeutic and diagnostic strategies addressing specific amino acids may offer potential means to mitigate the severity of the disease.

Keywords:  Amino acid; Crimean‐Congo hemorrhagic fever; LC‐MS/MS; severity

DOI:  https://doi.org/10.1002/jmv.29637
Int Rev Cell Mol Biol. 2024 ;pii: S1937-6448(24)00017-0. [Epub ahead of print]386 1-47

Cellular signaling in glioblastoma: A molecular and clinical perspective.

Debarati Ghosh, Brett Pryor, Nancy Jiang.

  Glioblastoma multiforme (GBM) is the most aggressive brain tumor with an average life expectancy of less than 15 months. Such high patient mortality in GBM is pertaining to the presence of clinical and molecular heterogeneity attributed to various genetic and epigenetic alterations. Such alterations in critically important signaling pathways are attributed to aberrant gene signaling. Different subclasses of GBM show predominance of different genetic alterations and therefore, understanding the complex signaling pathways and their key molecular components in different subclasses of GBM is extremely important with respect to clinical management. In this book chapter, we summarize the common and important signaling pathways that play a significant role in different subclasses and discuss their therapeutic targeting approaches in terms of preclinical studies and clinical trials.

Keywords:  Astrocytoma; Clinical trials; Glioblastoma multiforme (GBM); Isocitrate dehydrogenase (IDH); Pre-clinical studies; Signal transduction; Therapy

DOI:  https://doi.org/10.1016/bs.ircmb.2024.01.007
Cell Stress Chaperones. 2024 May 17. pii: S1355-8145(24)00075-0. [Epub ahead of print]

Bag1 protein loss sensitizes mouse embryonic fibroblasts to glutathione depletion.

Atsushi Inose-Maruyama, Hayato Irokawa, Kouki Takeda, Keiko Taguchi, Masanobu Morita, Masayuki Yamamoto, Masato Sasaki, Shusuke Kuge.

  Bcl2-associated athanogene-1 protein (Bag1) acts as a co-chaperone of heat shock protein 70 and heat shock cognate 70 (HSP70/HSC70) and regulates multiple cellular processes, including cell proliferation, apoptosis, environmental stress response, and drug resistance. Since Bag1 knockout mice exhibited fetal lethality, the in vivo function of Bag1 remains unclear. In this study, we established a mouse line expressing Bag1 gene missing exon 5, which corresponds to an encoding region for the interface of HSP70/HSC70. Despite mice carrying homoalleles of the Bag1 mutant (Bag1Δex5) expressing undetectable levels of Bag1, Bag1Δex5 homozygous mice developed without abnormalities. Bag1Δex5 protein was found to be highly unstable in cells and in vitro. We found that the growth of mouse embryonic fibroblasts (MEFs) derived from Bag1Δex5-homo mice was attenuated by doxorubicin and a glutathione (GSH) synthesis inhibitor, buthionine sulfoximine (BSO). In response to BSO, Bag1Δex5-MEFs exhibited a higher dropping rate of GSH relative to the oxidized glutathione level. In addition, Bag1 might mitigate cellular hydrogen peroxide levels. Taken together, our results demonstrate that the loss of Bag1 did not affect mouse development and that Bag1 is involved in intracellular GSH homeostasis, namely redox homeostasis.

Keywords:  Bag1; CRISPR/Cas9; glutathione; heme oxygenase-1; oxidative stress

DOI:  https://doi.org/10.1016/j.cstres.2024.05.003