bims-glucam 2025-01-05 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–01–05
fourteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Targeting glutamine metabolism crosstalk with tumor immune response.
Integrated bioinformatics analysis identifies ALDH18A1 as a prognostic hub gene in glutamine metabolism in lung adenocarcinoma.
RUNX2 enhances bladder cancer progression by promoting glutamine metabolism.
The Warburg Effect: Is it Always an Enemy?
Mitochondrial-cytochrome c oxidase II promotes glutaminolysis to sustain tumor cell survival upon glucose deprivation.
Efficacy of glutathione inhibitor eprenetapopt against the vulnerability of glutathione metabolism in SMARCA4-, SMARCB1- and PBRM1-deficient cancer cells.
Targeting Metabolic Adaptation of Colorectal Cancer with Vanadium-Doped Nanosystem to Enhance Chemotherapy and Immunotherapy.
Metabolic reprogramming in lung cancer and its clinical implication.
The molecular code of kidney cancer: A path of discovery for gene mutation and precision therapy.
Metabolism of cancer cells and immune cells in the initiation, progression, and metastasis of cancer.
Targeting estrogen-related receptors to mitigate tumor resistance: A comprehensive approach to bridging cellular energy metabolism.
Integrative pan-cancer analysis and experiment validation identified GLS as a biomarker in tumor progression, prognosis, immune microenvironment, and immunotherapy.
Effects of metabolism upon immunity: Targeting myeloid-derived suppressor cells for the treatment of breast cancer is a promising area of study.
NSUN2 lactylation drives cancer cell resistance to ferroptosis through enhancing GCLC-dependent glutathione synthesis.

Biochim Biophys Acta Rev Cancer. 2024 Dec 31. pii: S0304-419X(24)00188-4. [Epub ahead of print] 189257

Targeting glutamine metabolism crosstalk with tumor immune response.

Chenshuang Dong, Yan Zhao, Yecheng Han, Ming Li, Guiling Wang.

  Glutamine, akin to glucose, is a fundamental nutrient for human physiology. Tumor progression is often accompanied by elevated glutamine consumption, resulting in a disrupted nutritional balance and metabolic reprogramming within the tumor microenvironment. Furthermore, immune cells, which depend on glutamine for metabolic support, may experience functional impairments and dysregulation. Although the role of glutamine in tumors has been extensively studied, the specific impact of glutamine competition on immune responses, as well as the precise cellular alterations within immune cells, remains incompletely understood. In this review, we summarize the consequences of glutamine deprivation induced by tumor-driven glutamine uptake on immune cells, assessing the underlying mechanisms from the perspective of various components of the immune microenvironment. Additionally, we discuss the potential synergistic effects of glutamine supplementation and immunotherapy, offering insights into future research directions. This review provides compelling evidence for the integration of glutamine metabolism and immunotherapy as a promising strategy in cancer therapy.

Keywords:  Glutamine deprivation; Glutamine therapy; Immune cells; Immunotherapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2024.189257
Discov Oncol. 2025 Jan 02. 16(1): 1

Integrated bioinformatics analysis identifies ALDH18A1 as a prognostic hub gene in glutamine metabolism in lung adenocarcinoma.

Hao Ren, Deng-Feng Ge, Zi-Chen Yang, Zhen-Ting Cheng, Shou-Xiang Zhao, Bin Zhang.

Glutamine metabolism is pivotal in cancer biology, profoundly influencing tumor growth, proliferation, and resistance to therapies. Cancer cells often exhibit an elevated dependence on glutamine for essential functions such as energy production, biosynthesis of macromolecules, and maintenance of redox balance. Moreover, altered glutamine metabolism can contribute to the formation of an immune-suppressive tumor microenvironment characterized by reduced immune cell infiltration and activity. In this study on lung adenocarcinoma, we employed consensus clustering and applied 101 types of machine learning methods to systematically identify key genes associated with glutamine metabolism and develop a risk model. This comprehensive approach provided a clearer understanding of how glutamine metabolism associates with cancer progression and patient outcomes. Notably, we constructed a robust nomogram based on clinical information and patient risk scores, which achieved a stable area under the curve (AUC) greater than 0.8 for predicting patient survival across four datasets, demonstrating high predictive accuracy. This nomogram not only enhances our ability to stratify patient risk but also offers potential targets for therapeutic intervention aimed at disrupting glutamine metabolism and sensitizing tumors to existing treatments. Moreover, we identified ALDH18A1 as a prognostic hub gene of glutamine metabolism, characterized by high expression levels in glutamine cluster 3, which is associated with poor clinical outcomes and worse survival, and is included in the risk model. Such insights underscore the critical role of glutamine metabolism in cancer and highlight avenues for personalized medicine in oncology research.

DOI: https://doi.org/10.1007/s12672-024-01698-3
Neoplasia. 2024 Dec 28. pii: S1476-5586(24)00161-1. [Epub ahead of print]60 101120

RUNX2 enhances bladder cancer progression by promoting glutamine metabolism.

Zhigang Huang, Bin Liu, Xiaoju Li, Chenghua Jin, Quansen Hu, Zhiwei Zhao, Yimin Sun, Qian Wang.

  Bladder cancer is a prevalent malignancy within the urinary system. Prior research has suggested that glutamine metabolism plays a crucial role in driving bladder cancer progression. However, the precise molecular mechanism governing glutamine metabolism in bladder cancer is still inadequately understood. The research revealed a significant correlation between high levels of RUNX2 and SLC7A6 and advanced clinical stage, as well as poor prognosis, in bladder cancer patients. Furthermore, manipulating the levels of RUNX2 through overexpression or silencing demonstrated a significant impact on glutamine and bladder cancer progression. Mechanically, RUNX2 regulates the transcription of SLC7A6, resulting in enhanced glutamine metabolism and promoting the progression of bladder cancer. Overall, this research affirms the crucial function of RUNX2 as a key transcription factor to promoting glutamine and cancer development through modulation of SLC7A6. Targeting RUNX2 could represent a promising therapeutic approach for addressing aberrant glutamine metabolism in bladder cancer.

Keywords:  Bladder cancer; Glutamine metabolism; RUNX2

DOI:  https://doi.org/10.1016/j.neo.2024.101120
Front Biosci (Landmark Ed). 2024 Nov 27. 29(12): 402

The Warburg Effect: Is it Always an Enemy?

Christos Papaneophytou.

  The Warburg effect, also known as 'aerobic' glycolysis, describes the preference of cancer cells to favor glycolysis over oxidative phosphorylation for energy (adenosine triphosphate-ATP) production, despite having high amounts of oxygen and fully active mitochondria, a phenomenon first identified by Otto Warburg. This metabolic pathway is traditionally viewed as a hallmark of cancer, supporting rapid growth and proliferation by supplying energy and biosynthetic precursors. However, emerging research indicates that the Warburg effect is not just a strategy for cancer cells to proliferate at higher rates compared to normal cells; thus, it should not be considered an 'enemy' since it also plays complex roles in normal cellular functions and/or under stress conditions, prompting a reconsideration of its purely detrimental characterization. Moreover, this review highlights that distinguishing glycolysis as 'aerobic' and 'anaerobic' should not exist, as lactate is likely the final product of glycolysis, regardless of the presence of oxygen. Finally, this review explores the nuanced contributions of the Warburg effect beyond oncology, including its regulatory roles in various cellular environments and the potential effects on systemic physiological processes. By expanding our understanding of these mechanisms, we can uncover novel therapeutic strategies that target metabolic reprogramming, offering new avenues for treating cancer and other diseases characterized by metabolic dysregulation. This comprehensive reevaluation not only challenges traditional views but also enhances our understanding of cellular metabolism's adaptability and its implications in health and disease.

Keywords:  Warburg effect; cancer metabolism; cellular metabolism; glycolysis; metabolic reprogramming

DOI:  https://doi.org/10.31083/j.fbl2912402
Nat Commun. 2025 Jan 02. 16(1): 212

Mitochondrial-cytochrome c oxidase II promotes glutaminolysis to sustain tumor cell survival upon glucose deprivation.

Yong Yi, Guoqiang Wang, Wenhua Zhang, Shuhan Yu, Junjie Fei, Tingting An, Jianqiao Yi, Fengtian Li, Ting Huang, Jian Yang, Mengmeng Niu, Yang Wang, Chuan Xu, Zhi-Xiong Jim Xiao.

Glucose deprivation, a hallmark of the tumor microenvironment, compels tumor cells to seek alternative energy sources for survival and growth. Here, we show that glucose deprivation upregulates the expression of mitochondrial-cytochrome c oxidase II (MT-CO2), a subunit essential for the respiratory chain complex IV, in facilitating glutaminolysis and sustaining tumor cell survival. Mechanistically, glucose deprivation activates Ras signaling to enhance MT-CO2 transcription and inhibits IGF2BP3, an RNA-binding protein, to stabilize MT-CO2 mRNA. Elevated MT-CO2 increases flavin adenosine dinucleotide (FAD) levels in activating lysine-specific demethylase 1 (LSD1) to epigenetically upregulate JUN transcription, consequently promoting glutaminase-1 (GLS1) and glutaminolysis for tumor cell survival. Furthermore, MT-CO2 is indispensable for oncogenic Ras-induced glutaminolysis and tumor growth, and elevated expression of MT-CO2 is associated with poor prognosis in lung cancer patients. Together, these findings reveal a role for MT-CO2 in adapting to metabolic stress and highlight MT-CO2 as a putative therapeutic target for Ras-driven cancers.

DOI: https://doi.org/10.1038/s41467-024-55768-9
Sci Rep. 2024 Dec 28. 14(1): 31321

Efficacy of glutathione inhibitor eprenetapopt against the vulnerability of glutathione metabolism in SMARCA4-, SMARCB1- and PBRM1-deficient cancer cells.

Mariko Sasaki, Hideaki Ogiwara.

Mutation of genes related to the SWI/SNF chromatin remodeling complex is detected in 20% of all cancers. The SWI/SNF chromatin remodeling complex comprises about 15 subunits and is classified into three subcomplexes: cBAF, PBAF, and ncBAF. Previously, we showed that ovarian clear cell carcinoma cells deficient in ARID1A, a subunit of the cBAF complex, are synthetic lethal with several genes required for glutathione (GSH) synthesis and are therefore sensitive to the GSH inhibitor eprenetapopt (APR-246). However, we do not know whether cancer cells deficient in SWI/SNF components other than ARID1A are selectively sensitive to treatment with eprenetapopt. Here, we show that SMARCA4-, SMARCB1-, and PBRM1-deficient cells are more sensitive to eprenetapopt than SWI/SNF-proficient cells. We found that deficiency of SMARCA4, SMARCB1, or PBRM1 attenuates transcription of the SLC7A11 gene (which supplies cysteine as a raw metabolic material for GSH synthesis) by the failure of recruitment of cBAF and PBAF to the promotor and enhancer regions of the SLC7A11 locus, thereby reducing basal levels of GSH. In addition, eprenetapopt decreased the amount of intracellular GSH and increased the intracellular amount of reactive oxygen species (ROS), followed by induction of apoptosis. Taken together, eprenetapopt could be a promising selective agent for SWI/SNF-deficient cancer cells derived from SMARCA4-deficient lung cancers, SMARCB1-deficient rhabdoid tumors, and PBRM1-deficient kidney cancers.

DOI: https://doi.org/10.1038/s41598-024-82753-5
Adv Sci (Weinh). 2024 Dec 30. e2409329

Targeting Metabolic Adaptation of Colorectal Cancer with Vanadium-Doped Nanosystem to Enhance Chemotherapy and Immunotherapy.

Qian Cheng, Yuzhe Chen, Danyi Zou, Qilin Li, Xiaolei Shi, Qushuhua Qin, Miaodeng Liu, Lin Wang, Zheng Wang.

  The anti-tumor efficacy of current pharmacotherapy is severely hampered due to the adaptive evolution of tumors, urgently needing effective therapeutic strategies capable of breaking such adaptability. Metabolic reprogramming, as an adaptive survival mechanism, is closely related to therapy resistance of tumors. Colorectal cancer (CRC) cells exhibit a high energy dependency that is sustained by an adaptive metabolic conversion between glucose and glutamine, helping tumor cells to withstand nutrient-deficient microenvironments and various treatments. We discover that transition metal vanadium (V) effectively inhibits glucose metabolism in CRC and synergizes with glutaminase inhibitors (BPTES) to disrupt CRC's energy dependency. Thus, a dual energy metabolism suppression nanosystem (VSi-BP@HA) is engineered by loading BPTES into V-doped hollow mesoporous silica nanoparticles. This nanosystem effectively dampens CRC energy metabolism, eradicating 33% of tumors in mice. Strikingly, the cell biological and preclinical model datasets provide compelling evidence showing that VSi-BP@HA not only reverses CRC cells chemo-resistance but also drastically potentiates anti-PD1 immunotherapy. Therefore, this nanosystem provides not only a promising approach to suppress CRC, but also a potential adjunct tool for enhancing chemotherapy and immunotherapy.

Keywords:  enhancing chemotherapy and immunotherapy; glucose and glutamine; metabolic reprogramming; nanosystem; therapy resistance

DOI:  https://doi.org/10.1002/advs.202409329
Front Pharmacol. 2024 ;15 1516650

Metabolic reprogramming in lung cancer and its clinical implication.

Qingqiu Huang, Lisha Fan, Mingjing Gong, Juntong Ren, Chen Chen, Shenglong Xie.

  Lung cancer has posed a significant challenge to global health, and related study has been a hot topic in oncology. This article focuses on metabolic reprogramming of lung cancer cells, a process to adapt to energy demands and biosynthetic needs, supporting the proliferation and development of tumor cells. In this study, the latest studies on lung cancer tumor metabolism were reviewed, including the impact of metabolic products and metabolic enzymes on the occurrence and development of lung cancer, as well as the progress in the field of lung cancer treatment targeting relevant metabolic pathways. This provides some promising potential directions into exploring lung cancer tumor metabolism and helps researchers to better understand lung cancer.

Keywords:  amino acid metabolism; glucose; lipid metabolism; lung cancer; metabolic reprogramming

DOI:  https://doi.org/10.3389/fphar.2024.1516650
Mol Aspects Med. 2025 Jan 01. pii: S0098-2997(24)00094-3. [Epub ahead of print]101 101335

The molecular code of kidney cancer: A path of discovery for gene mutation and precision therapy.

Deqian Xie, Guandu Li, Zunwen Zheng, Xiaoman Zhang, Shijin Wang, Bowen Jiang, Xiaorui Li, Xiaoxi Wang, Guangzhen Wu.

  Renal cell carcinoma (RCC) is a malignant tumor with highly heterogeneous and complex molecular mechanisms. Through systematic analysis of TCGA, COSMIC and other databases, 24 mutated genes closely related to RCC were screened, including VHL, PBRM1, BAP1 and SETD2, which play key roles in signaling pathway transduction, chromatin remodeling and DNA repair. The PI3K/AKT/mTOR signaling pathway is particularly important in the pathogenesis of RCC. Mutations in genes such as PIK3CA, MTOR and PTEN are closely associated with metabolic abnormalities and tumor cell proliferation. Clinically, mTOR inhibitors and VEGF-targeted drugs have shown significant efficacy in personalized therapy. Abnormal regulation of metabolic reprogramming, especially glycolysis and glutamine metabolic pathways, provides tumor cells with continuous energy supply and survival advantages, and GLS1 inhibitors have shown promising results in preclinical studies. This paper also explores the potential of immune checkpoint inhibitors in combination with other targeted drugs, as well as the promising application of nanotechnology in drug delivery and targeted therapy. In addition, unique molecular mechanisms are revealed and individualized therapeutic strategies are explored for specific subtypes such as TFE3, TFEB rearrangement type and SDHB mutant type. The review summarizes the common gene mutations in RCC and their molecular mechanisms, emphasizes their important roles in tumor diagnosis, treatment and prognosis, and looks forward to the application prospects of multi-pathway targeted therapy, metabolic targeted therapy, immunotherapy and nanotechnology in RCC treatment, providing theoretical support and clinical guidance for individualized treatment and new drug development.

Keywords:  Gene mutation; HIF signaling pathway; Immune microenvironment; Immunotherapy; Metabolic reprogramming; PI3K/AKT/mTOR pathway; Renal cell carcinoma; Targeted therapy

DOI:  https://doi.org/10.1016/j.mam.2024.101335
Theranostics. 2025 ;15(1): 155-188

Metabolism of cancer cells and immune cells in the initiation, progression, and metastasis of cancer.

Mingxia Jiang, Huapan Fang, Huayu Tian.

  The metabolism of cancer and immune cells plays a crucial role in the initiation, progression, and metastasis of cancer. Cancer cells often undergo metabolic reprogramming to sustain their rapid growth and proliferation, along with meeting their energy demands and biosynthetic needs. Nevertheless, immune cells execute their immune response functions through the specific metabolic pathways, either to recognize, attack, and eliminate cancer cells or to promote the growth or metastasis of cancer cells. The alteration of cancer niches will impact the metabolism of both cancer and immune cells, modulating the survival and proliferation of cancer cells, and the activation and efficacy of immune cells. This review systematically describes the key characteristics of cancer cell metabolism and elucidates how such metabolic traits influence the metabolic behavior of immune cells. Moreover, this article also highlights the crucial role of immune cell metabolism in anti-tumor immune responses, particularly in priming T cell activation and function. By comprehensively exploring the metabolic crosstalk between cancer and immune cells in cancer niche, the aim is to discover novel strategies of cancer immunotherapy and provide effective guidance for clinical research in cancer treatment. In addition, the review also discusses current challenges such as the inadequacy of relevant diagnostic technologies and the issue of multidrug resistance, and proposes potential solutions including bolstering foundational cancer research, fostering technological innovation, and implementing precision medicine approaches. In-depth research into the metabolic effects of cancer niches can improve cancer treatment outcomes, prolong patients' survival period and enhance their quality of life.

Keywords:  Anti-tumor immune responses; Cancer immunotherapy; Cancer niches; Metabolic reprogramming; Metabolism of cancer and immune cells

DOI:  https://doi.org/10.7150/thno.103376
Biochim Biophys Acta Rev Cancer. 2024 Dec 30. pii: S0304-419X(24)00187-2. [Epub ahead of print] 189256

Targeting estrogen-related receptors to mitigate tumor resistance: A comprehensive approach to bridging cellular energy metabolism.

Yuan Ren, Xiaodan Mao, Wenyu Lin, Yi Chen, Rongfeng Chen, Pengming Sun.

  The war between humanity and malignant tumors has been ongoing, with continuous advancements in classic chemotherapy and radiotherapy regimens, targeted drugs, endocrine therapy, and immunotherapy. However, tumor cells can develop primary or secondary resistance to these treatment options, making the issue of tumor resistance a major factor affecting patient prognosis and leading to recurrence. Estrogen-related receptors (ERRs) are members of the nuclear receptor superfamily, primarily involved in regulating glucose, lipid, and amino acid metabolism, serving as a central hub for intracellular energy metabolism. ERRs not only mediate insulin resistance but also participate in the mechanisms of drug resistance in various tumors, including breast cancer, osteosarcoma, endometrial cancer, lung cancer, and liver cancer, and even mediate resistance to radiation and immunotherapy. They mainly resist tumor treatment methods through metabolic reprogramming within cells, affecting mitochondrial energy metabolism, regulating metabolites such as cholesterol, glutamine, and lactate, or other signaling pathways, or by influencing the immune microenvironment. ERRs are promising targets for addressing the dilemma of tumor resistance. Currently, electrochemical luminescence biosensors for detecting ERRα in bodily fluids have been developed, making large-scale, low-cost detection of ERRα possible. Additionally, targeted inhibitors of ERRs have shown significant effects in suppressing cancer cell proliferation and reversing tumor resistance. This article reviews the research progress of ERRs in tumor resistance, providing important references for developing more effective anti-tumor treatment strategies.

Keywords:  Energy metabolism; Estrogen-related receptors; Immunotherapy; Insulin resistance; Tumor resistance

DOI:  https://doi.org/10.1016/j.bbcan.2024.189256
Sci Rep. 2025 Jan 02. 15(1): 525

Integrative pan-cancer analysis and experiment validation identified GLS as a biomarker in tumor progression, prognosis, immune microenvironment, and immunotherapy.

Dongming Li, Donghui Cao, Yangyu Zhang, Xinyi Yu, Yanhua Wu, Zhifang Jia, Jing Jiang, Xueyuan Cao.

  Glutaminase (GLS), a crucial gene regulating glutaminolysis, has received much attention as it was found to regulate tumor metabolism and copper-induced cell death. However, its biological roles and mechanisms in human cancers remain obscure. Consequently, the integrated pan-cancer analyses and biological experiments were conducted to elucidate its oncological functions. We found GLS was differentially expressed in human cancers and upregulated GLS predicted poor survival, clinicopathological progression, and tumor heterogeneity. Single-cell analysis found GLS was closely related to various biological functions and pathways. Spatial transcriptomic analysis found GLS expression was mainly derived from tumor cells, which implies tumor cells may have a stronger ability to utilize glutamine than antitumor immune cells in the tumor microenvironment (TME). Meanwhile, we noticed GLS expression was strongly related to the infiltration of various immune cells and stromal cells, the expression of immunomodulatory genes, the activity of some conventional antitumor agents, and the therapeutic response of immunotherapy. Moreover, enrichment analyses suggested GLS was related to various metabolic reprogramming, innate and adaptive immunity suppression, and extracellular matrix remodeling. Finally, we observed GLS was highly expressed in our gastric cancer (GC) cohort. As an independent risk factor for GC prognosis, high-GLS was closely related to pathological progression. Inhibiting GLS expression in GC cells effectively prevented proliferation, migration, and invasion and triggered apoptosis. In conclusion, GLS is an underlying biomarker for oncological progression, prognosis, TME, antitumor drug sensitivity, and immunotherapy response. Targeting GLS can facilitate the implementation of individualized and combined treatment strategies.

Keywords:  Biomarker; GLS; Gastric cancer; Immunotherapy; Pan-cancer analysis; Tumor microenvironment

DOI:  https://doi.org/10.1038/s41598-024-84916-w
Int Immunopharmacol. 2024 Dec 30. pii: S1567-5769(24)02414-7. [Epub ahead of print]147 113892

Effects of metabolism upon immunity: Targeting myeloid-derived suppressor cells for the treatment of breast cancer is a promising area of study.

Yulin Wang, Qiutong Dong, Menghan Yuan, Jingxian Hu, Peizhe Lin, Yijing Yan, Yu Wang, Yanyan Wang.

  Breast cancer (BC) ranks among the most prevalent malignancies affecting women, with advanced-stage patients facing an increased mortality risk. Myeloid-derived suppressor cells (MDSCs) contribute significantly to poor prognostic outcomes. Research has concentrated predominantly on the immunological mechanisms underlying MDSC functions, but a comprehensive investigation into the metabolic interactions between BC cells and MDSCs is lacking. In a hypoxic tumor microenvironment (TME), BC cells can enhance aerobic-glycolysis rates, upregulate expression of key lipid metabolism enzymes such as cluster of differentiation (CD) 36 and 5-lipoxygenase (5-LOX), accelerate glutamine (Gln) uptake, and elevate extracellular adenosine (eADO) levels, thereby fostering MDSC proliferation and amplifying immune suppression. Concurrently, alterations in the metabolic state of MDSCs also influence BC progression. To ensure adequate proliferative resources, MDSCs upregulate the pentose phosphate pathway and expedite glycolysis for energy supply while increasing the expression of fatty acid transport proteins (FATPs) such as CD36 and fatty acid transporter 2 (FATP2) to maintain intracellular lipid availability, thereby enhancing their adaptability within the TME. Furthermore, MDSCs undermine T-cell anti-tumor efficacy by depleting essential amino acids (AAs), such as arginine (Arg), tryptophan (Trp), and cysteine (Cys), required for T-cell function. This review elucidates how pharmacological agents such as metformin, liver X receptor (LXR) agonists, and 6-diazo-5-oxo-L-norleucine (DON) can augment anti-cancer treatment efficacy by targeting metabolic pathways in MDSCs. We systematically delineate the mechanisms governing interactions between BC cells and MDSCs from a metabolic standpoint while summarizing therapeutic strategies to modulate metabolism within MDSCs. Our review provides a framework for optimizing MDSC applications in BC immunotherapy.

Keywords:  Breast cancer; Immunity; Metabolism; Myeloid-derived suppressor cells; Targeted therapy

DOI:  https://doi.org/10.1016/j.intimp.2024.113892
Redox Biol. 2024 Dec 19. pii: S2213-2317(24)00457-9. [Epub ahead of print]79 103479

NSUN2 lactylation drives cancer cell resistance to ferroptosis through enhancing GCLC-dependent glutathione synthesis.

Kaifeng Niu, Zixiang Chen, Mengge Li, Guannan Ma, Yuchun Deng, Ji Zhang, Di Wei, Jiaqi Wang, Yongliang Zhao.

  Lactate-mediated lactylation on target proteins is recently identified as the novel posttranslational modification with profound biological functions. RNA 5-methylcytosine (m5C) modification possesses dynamic and reversible nature, suggesting that activity of its methyltransferase NSUN2 is actively regulated. However, how NSUN2 activity is response to acidic condition in tumor microenvironment and then regulates cancer cell survival remain to be clarified. Here, we demonstrate that NSUN2 activity is enhanced by lactate-mediated lactylation at lysine 508, which then targets glutamate-cysteine ligase catalytic subunit (GCLC) mRNA to facilitates GCLC m5C formation and mRNA stabilization. The activated GCLC induces higher level of intracellular GSH accompanied by decreased lipid peroxidation and resistant phenotype to ferroptosis induction by doxorubicin (Dox) in gastric cancer cells. Specifically, the effect of NSUN2 lactylation-GCLC-GSH pathway is nearly lost when NSUN2 K508R or GCLC C-A mutant (five cytosine sites) was introduced into the cancer cells. We further identify the catalytic subunit N-α-acetyltransferase 10 (NAA10) as the lactytransferase of NSUN2, and lactate treatment substantially enhances their association and consequent NSUN2 activation. Taken together, our findings convincingly elucidate the signaling axis of NAA10-NSUN2-GCLC that potently antagonizes the ferroptosis under acidic condition, and therefore, targeting NSUN2 lactylation might be an effective strategy in improving the prognosis of cancer patients.

Keywords:  Ferroptosis; GCLC; Glutathione synthesis; Lactylation; NSUN2; RNA 5-methylcytosine

DOI:  https://doi.org/10.1016/j.redox.2024.103479