bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2023–03–26
fourteen papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Rethinking glutamine metabolism and the regulation of glutamine addiction by oncogenes in cancer.
  2. Role and therapeutic targeting of glutamine metabolism in non‑small cell lung cancer (Review).
  3. Targeting Glutamine Metabolism in Prostate Cancer.
  4. Deletion of the tyrosine phosphatase Shp2 in cervical cancer cells promotes reprogramming of glutamine metabolism.
  5. Glutamine deprivation induces ferroptosis in pancreatic cancer cells.
  6. Feasibility of [18F]FSPG PET for Early Response Assessment to Combined Blockade of EGFR and Glutamine Metabolism in Wild-Type KRAS Colorectal Cancer.
  7. A novel lonidamine derivative targeting mitochondria to eliminate cancer stem cells by blocking glutamine metabolism.
  8. Histone deacetylase 6 inhibition exploits selective metabolic vulnerabilities in LKB1 mutant, KRAS driven non-small cell lung cancer.
  9. Non-essential amino acid availability influences proteostasis and breast cancer cell survival during proteotoxic stress.
  10. Reprogramming of tissue metabolism during cancer metastasis.
  11. A self-amplified ferroptosis nanoagent that inhibits the tumor upstream glutathione synthesis to reverse cancer chemoresistance.
  12. Hepatocellular carcinoma subtypes based on metabolic pathways reveals potential therapeutic targets.
  13. Alpha-ketoglutarate as a potent regulator for lifespan and healthspan: Evidences and perspectives.
  14. Inspired by Game Theory: Glutathione-induced in Situ Michael Addition between Nanoparticles for Pyroptosis and Immunotherapy.
  1. Front Oncol. 2023 ;13 1143798
    Rethinking glutamine metabolism and the regulation of glutamine addiction by oncogenes in cancer.
    Rui Ni, Ziwei Li, Li Li, Dan Peng, Yue Ming, Lin Li, Yao Liu.
      Glutamine, the most abundant non-essential amino acid in human blood, is crucial for cancer cell growth and cancer progression. Glutamine mainly functions as a carbon and nitrogen source for biosynthesis, energy metabolism, and redox homeostasis maintenance in cancer cells. Dysregulated glutamine metabolism is a notable metabolic characteristic of cancer cells. Some carcinogen-driven cancers exhibit a marked dependence on glutamine, also known as glutamine addiction, which has rendered the glutamine metabolic pathway a breakpoint in cancer therapeutics. However, some cancer cells can adapt to the glutamine unavailability by reprogramming metabolism, thus limiting the success of this therapeutic approach. Given the complexity of metabolic networks and the limited impact of inhibiting glutamine metabolism alone, the combination of glutamine metabolism inhibition and other therapeutic methods may outperform corresponding monotherapies in the treatment of cancers. This review summarizes the uptake, transport, and metabolic characteristics of glutamine, as well as the regulation of glutamine dependence by some important oncogenes in various cancers to emphasize the therapeutic potential of targeting glutamine metabolism. Furthermore, we discuss a glutamine metabolic pathway, the glutaminase II pathway, that has been substantially overlooked. Finally, we discuss the applicability of polytherapeutic strategies targeting glutamine metabolism to provide a new perspective on cancer therapeutics.
    Keywords:  cancer therapy; glutamine addiction; glutamine metabolism; metabolism inhibiton; oncogene
    DOI:  https://doi.org/10.3389/fonc.2023.1143798
  2. Oncol Lett. 2023 Apr;25(4): 159
    Role and therapeutic targeting of glutamine metabolism in non‑small cell lung cancer (Review).
    Lei Zhou, Qi Zhang, Qing Zhu, Yuan Zhan, Yong Li, Xuan Huang.
      The Warburg effect indicates that cancer cells survive through glycolysis under aerobic conditions; as such, the topic of cancer metabolism has aroused interest. It is requisite to further explore cancer metabolism, as it helps to simultaneously explain the process of carcinogenesis and guide therapy. The flexible metabolism of cancer cells, which is the result of metabolic reprogramming, can meet the basic needs of cells, even in a nutrition-deficient environment. Glutamine is the most abundant non-essential amino acid in the circulation, and along with glucose, comprise the two basic nutrients of cancer cell metabolism. Glutamine is crucial in non-small cell lung cancer (NSCLC) cells and serves an important role in supporting cell growth, activating signal transduction and maintaining redox homeostasis. In this perspective, the present review aims to provide a new therapeutic strategy of NSCLC through inhibiting the metabolism of glutamine. This review not only summarizes the significance of glutamine metabolism in NSCLC cells, but also enumerates traditional glutamine inhibitors along with new targets. It also puts forward the concept of combination therapy and patient stratification with the aim of comprehensively showing the effect and prospect of targeted glutamine metabolism in NSCLC therapy. This review was completed by searching for keywords including 'glutamine', 'NSCLC' and 'therapy' on PubMed, and screening out articles.
    Keywords:  Warburg effect; glutamine metabolism; metabolism inhibitor; non-small cell lung cancer; therapeutic strategies
    DOI:  https://doi.org/10.3892/ol.2023.13745
  3. Front Biosci (Elite Ed). 2023 Jan 04. 15(1): 2
    Targeting Glutamine Metabolism in Prostate Cancer.
    Neil Bhowmick, Edwin Posadas, Leigh Ellis, Stephen J Freedland, Dolores Di Vizio, Michael R Freeman, Dan Theodorescu, Robert Figlin, Jun Gong.
      Glutamine is a conditionally essential amino acid important for cancer cell proliferation through intermediary metabolism leading to de novo synthesis of purine and pyrimidine nucleotides, hexosamine biosytnehsis, fatty acid synthesis through reductive carboxylation, maintenance of redox homeostasis, glutathione synthesis, production of non-essential amino acids, and mitochondrial oxidative phosphorylation. Prostate cancer has increasingly been characterized as a tumor type that is heavily dependent on glutamine for growth and survival. In this review, we highlight the preclinical evidence that supports a relationship between glutamine signaling and prostate cancer progression. We focus on the regulation of glutamine metabolism in prostate cancer through key pathways involving the androgen receptor pathway, MYC, and the PTEN/PI3K/mTOR pathway. We end with a discussion on considerations for translation of targeting glutamine metabolism as a therapeutic strategy to manage prostate cancer. Here, it is important to understand that the tumor microenvironment also plays a role in facilitating glutamine signaling and resultant prostate cancer growth. The druggability of prostate cancer glutamine metabolism is more readily achievable with our greater understanding of tumor metabolism and the advent of selective glutaminase inhibitors that have proven safe and tolerable in early-phase clinical trials.
    Keywords:  MYC; PTEN; androgen receptor; castrate-resistance; glutaminase; glutamine; mTOR; prostate cancer
    DOI:  https://doi.org/10.31083/j.fbe1501002
  4. FASEB J. 2023 Apr;37(4): e22880
    Deletion of the tyrosine phosphatase Shp2 in cervical cancer cells promotes reprogramming of glutamine metabolism.
    Xuehui Gao, Jie Kang, Xiangke Li, Chuan Chen, Duqiang Luo.
      Shp2 is a nonreceptor protein tyrosine phosphatase that is overexpressed in cervical cancer. However, the role of Shp2 in the regulation of cervical cancer metabolism and tumorigenesis is unclear. EGFR signaling pathways are commonly dysregulated in cervical cancer. We showed that Shp2 knockout in cervical cancer cells decreased EGFR expression and downregulated downstream RAS-ERK activation. Although AKT was activated in Shp2 knockout cells, inhibition of AKT activation could not make cells more sensitive to death. Shp2 depletion inhibited cervical cancer cell proliferation and reduced tumor growth in a xenograft mouse model. 1 H NMR spectroscopic analysis showed that glutamine, glutamate, succinate, creatine, glutathione, and UDP-GlcNAc were significantly changed in Shp2 knockout cells. The intracellular glutamine level was higher in Shp2 knockout cells than in control cells. Further analysis demonstrated that Shp2 knockout promoted glutaminolysis and glutathione production by up-regulating the glutamine metabolism-related genes such as glutaminase (GLS). However, inhibition of GLS did not always make cells sensitive to death, which was dependent on glucose concentration. The level of oxidative phosphorylation was significantly increased, accompanied by an increased generation of reactive oxygen species in Shp2 knockout cells. Shp2 deficiency increased c-Myc and c-Jun expression, which may be related to the upregulation of glutamine metabolism. These findings suggested that Shp2 regulates cervical cancer proliferation, glutamine metabolism, and tumorigenicity.
    Keywords:  EGFR; Shp2; cervical cancer; glutaminolysis; metabolic reprogramming
    DOI:  https://doi.org/10.1096/fj.202202078RR
  5. Acta Biochim Biophys Sin (Shanghai). 2023 Mar 25.
    Glutamine deprivation induces ferroptosis in pancreatic cancer cells.
    Zhiwen Xiao, Shengming Deng, He Liu, Ruijie Wang, Yu Liu, Zhengjie Dai, Wenchao Gu, Quanxing Ni, Xianjun Yu, Chen Liu, Guopei Luo.
      Ferroptosis is a type of programmed cell death closely related to amino acid metabolism. Pancreatic cancer cells have a strong dependence on glutamine, which serves as a carbon and nitrogen substrate to sustain rapid growth. Glutamine also aids in self-protection mechanisms. However, the effect of glutamine on ferroptosis in pancreatic cancer remains largely unknown. Here, we aim to explore the association between ferroptosis and glutamine deprivation in pancreatic cancer. The growth of pancreatic cancer cells in culture media with or without glutamine is evaluated using Cell Counting Kit-8. Reactive oxygen species (ROS) are measured by 2',7'-dichlorodihydrofluorescein diacetate staining. Ferroptosis is assessed by BODIPY-C11 dye using confocal microscopy and flow cytometry. Amino acid concentrations are measured using ultrahigh-performance liquid chromatography-tandem mass spectrometry. Isotope-labelled metabolic flux analysis is performed to track the metabolic flow of glutamine. Additionally, RNA sequencing is performed to analyse the genetic alterations. Glutamine deprivation inhibits pancreatic cancer growth and induces ferroptosis both in vitro and in vivo. Additionally, glutamine decreases ROS formation via glutathione production in pancreatic cancer cells. Interestingly, glutamine inhibitors (diazooxonorleucine and azaserine) promotes ROS formation and ferroptosis in pancreatic cancer cells. Furthermore, ferrostatin, a ferroptosis inhibitor, rescues ferroptosis in pancreatic cancer cells. Glutamine deprivation leads to changes in molecular pathways, including cytokine-cytokine receptor interaction pathways ( CCL5, CCR4, LTA, CXCR4, IL-6R, and IL-7R). Thus, exogenous glutamine is required for the detoxification of ROS in pancreatic cancer cells, thereby preventing ferroptosis.
    Keywords:  ferroptosis; glutamine; glutathione; pancreatic cancer; reactive oxygen species
    DOI:  https://doi.org/10.3724/abbs.2023029
  6. Tomography. 2023 Feb 24. 9(2): 497-508
    Feasibility of [18F]FSPG PET for Early Response Assessment to Combined Blockade of EGFR and Glutamine Metabolism in Wild-Type KRAS Colorectal Cancer.
    Seong-Woo Bae, Jianbo Wang, Dimitra K Georgiou, Xiaoxia Wen, Allison S Cohen, Ling Geng, Mohammed Noor Tantawy, H Charles Manning.
      Early response assessment is critical for personalizing cancer therapy. Emerging therapeutic regimens with encouraging results in the wild-type (WT) KRAS colorectal cancer (CRC) setting include inhibitors of epidermal growth factor receptor (EGFR) and glutaminolysis. Towards predicting clinical outcome, this preclinical study evaluated non-invasive positron emission tomography (PET) with (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) in treatment-sensitive and treatment-resistant WT KRAS CRC patient-derived xenografts (PDXs). Tumor-bearing mice were imaged with [18F]FSPG PET before and one week following the initiation of treatment with either EGFR-targeted monoclonal antibody (mAb) therapy, glutaminase inhibitor therapy, or the combination. Imaging was correlated with tumor volume and histology. In PDX that responded to therapy, [18F]FSPG PET was significantly decreased from baseline at 1-week post-therapy, prior to changes in tumor volume. In contrast, [18F]FSPG PET was not decreased in non-responding PDX. These data suggest that [18F]FSPG PET may serve as an early metric of response to EGFR and glutaminase inhibition in the WT KRAS CRC setting.
    Keywords:  EGFR; FSPG; PET; colorectal cancer; glutaminolysis
    DOI:  https://doi.org/10.3390/tomography9020041
  7. Pharmacol Res. 2023 Mar 21. pii: S1043-6618(23)00096-8. [Epub ahead of print] 106740
    A novel lonidamine derivative targeting mitochondria to eliminate cancer stem cells by blocking glutamine metabolism.
    Qiang Wang, Shiyou Li, Chen Xu, Ao Hua, Chong Wang, Yuxuan Xiong, Qingyuan Deng, Xiang Chen, Tian Yang, Jiangling Wan, Ze-Yang Ding, Bi-Xiang Zhang, Xiangliang Yang, Zifu Li.
      Cancer stem cells (CSCs) have been blamed as the main culprit of tumor initiation, progression, metastasis, chemoresistance, and recurrence. However, few anti-CSCs agents have achieved clinical success so far. Here we report a novel derivative of lonidamine (LND), namely HYL001, which selectively and potently inhibits CSCs by targeting mitochondria, with 380-fold and 340-fold lower IC50 values against breast cancer stem cells (BCSCs) and hepatocellular carcinoma stem cells (HCSCs), respectively, compared to LND. Mechanistically, we reveal that HYL001 downregulates glutaminase (GLS) expression to block glutamine metabolism, blunt tricarboxylic acid cycle, and amplify mitochondrial oxidative stress, leading to apoptotic cell death. Therefore, HYL001 displays significant antitumor activity in vivo, both as a single agent and combined with paclitaxel. Furthermore, HYL001 represses CSCs of fresh tumor tissues derived from liver cancer patients. This study provides critical implications for CSCs biology and development of potent anti-CSCs drugs.
    Keywords:  Cancer stem cells; Glutamine metabolism; HYL001; Mitochondrial targeting
    DOI:  https://doi.org/10.1016/j.phrs.2023.106740
  8. J Thorac Oncol. 2023 Mar 21. pii: S1556-0864(23)00197-1. [Epub ahead of print]
    Histone deacetylase 6 inhibition exploits selective metabolic vulnerabilities in LKB1 mutant, KRAS driven non-small cell lung cancer.
    Hua Zhang, Christopher S Nabel, Dezhi Li, Ruth Í O'Connor, Caroline R Crosby, Sarah M Chang, Yuan Hao, Robyn Stanley, Soumyadip Sahu, Daniel S Levin, Ting Chen, Sittinon Tang, Hsin-Yi Huang, Mary Meynardie, Janaye Stephens, Fiona Sherman, Alison Chafitz, Naoise Costelloe, Daniel A Rodrigues, Hilda Fogarty, Miranda G Kiernan, Fiona Cronin, Eleni Papadopoulos, Magdalena Ploszaj, Vajira Weerasekara, Jiehui Deng, Patrick Kiely, Nabeel Bardeesy, Matthew G Vander Heiden, Triona Ni Chonghaile, Catríona M Dowling, Kwok-Kin Wong.
       INTRODUCTION: In KRAS-mutant non-small lung cancer (NSCLC), co-occurring alterations in LKB1 confer a negative prognosis compared to other mutations such as TP53. LKB1 is a tumor suppressor that coordinates several signaling pathways in response to energetic stress. Our recent work on pharmacologic and genetical inhibition of HDAC6 demonstrated impaired activity of numerous enzymes involved in glycolysis. Based on these prior findings, we explored the therapeutic window for HDAC6 inhibition in metabolically-active KRAS-mutant lung tumors.
    EXPERIMENTAL DESIGN: Using cell lines derived from mouse autochthonous tumors bearing the KRAS/LKB1 (KL) and KRAS/TP53 (KP) mutant genotypes to control for confounding germline and somatic mutations in human models, we characterize the metabolic phenotypes at baseline and in response to HDAC6 inhibition. The impact of HDAC6 inhibition was measured on cancer cell growth in vitro and on tumor growth in vivo.
    RESULTS: Surprisingly, KL-mutant cells demonstrated reduced levels of redox-sensitive cofactors at baseline. This associated with increased sensitivity to pharmacologic HDAC6 inhibition with ACY-1215 and blunted ability to increase compensatory metabolism and buffer oxidative stress. Seeking synergistic metabolic combination treatments, we found enhanced cell killing and anti-tumor efficacy with glutaminase inhibition in KL lung cancer models in vitro and in vivo.
    CONCLUSIONS: Exploring the differential metabolism of KL and KP mutant NSCLC, we identified decreased metabolic reserve in KL mutant tumors. HDAC6 inhibition exploited a therapeutic window in KL NSCLC based on a diminished ability to compensate for impaired glycolysis, nominating a novel strategy for treatment of KRAS-mutant NSCLC with co-occurring LKB1 mutations.
    Keywords:  HDAC6; KRAS; LKB1; TP53; glutaminase inhibition; glycolysis; non-small cell lung cancer; oxidative stress
    DOI:  https://doi.org/10.1016/j.jtho.2023.03.014
  9. Mol Cancer Res. 2023 Mar 24. pii: MCR-22-0843. [Epub ahead of print]
    Non-essential amino acid availability influences proteostasis and breast cancer cell survival during proteotoxic stress.
    Sara Sannino, Allison M Manuel, Chaowei Shang, Stacy G Wendell, Peter Wipf, Jeffrey L Brodsky.
      Protein homeostasis (proteostasis) regulates tumor growth and proliferation when cells are exposed to proteotoxic stress, such as during treatment with certain chemotherapeutics. Consequently, cancer cells depend to a greater extent on stress signaling, and require the integrated stress response (ISR), amino acid metabolism, and efficient protein folding and degradation pathways to survive. To define how these interconnected pathways are wired when cancer cells are challenged with proteotoxic stress, we investigated how amino acid abundance influences cell survival when Hsp70, a master proteostasis regulator, is inhibited. We previously demonstrated that cancer cells exposed to a specific Hsp70 inhibitor induce the ISR via the action of two sensors, GCN2 and PERK, in stress-resistant and sensitive cells, respectively. In resistant cells, the induction of GCN2 and autophagy supported resistant cell survival, yet the mechanism by which these events were induced remained unclear. We now report that amino acid availability reconfigures the proteostasis network. Amino acid supplementation, and in particular arginine addition, triggered cancer cell death by blocking autophagy. Consistent with the importance of amino acid availability, which when limited activates GCN2, resistant cancer cells succumbed when challenged with a potentiator for another amino acid sensor, mTORC1, in conjunction with Hsp70 inhibition. Implications: These data position amino acid abundance, GCN2, mTORC1, and autophagy as integrated therapeutic targets whose coordinated modulation regulates the survival of proteotoxic-resistant breast cancer cells.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-22-0843
  10. Trends Cancer. 2023 Mar 17. pii: S2405-8033(23)00028-6. [Epub ahead of print]
    Reprogramming of tissue metabolism during cancer metastasis.
    Koelina Ganguly, Alec C Kimmelman.
      Cancer is a systemic disease that involves malignant cell-intrinsic and -extrinsic metabolic adaptations. Most studies have tended to focus on elucidating the metabolic vulnerabilities in the primary tumor microenvironment, leaving the metastatic microenvironment less explored. In this opinion article, we discuss the current understanding of the metabolic crosstalk between the cancer cells and the tumor microenvironment, both at local and systemic levels. We explore the possible influence of the primary tumor secretome to metabolically and epigenetically rewire the nonmalignant distant organs during prometastatic niche formation and successful metastatic colonization by the cancer cells. In an attempt to understand the process of prometastatic niche formation, we have speculated how cancer may hijack the inherent regenerative propensity of tissue parenchyma during metastatic colonization.
    Keywords:  metabolism; metastasis; prometastatic niche; stroma; tissue regeneration; wound response
    DOI:  https://doi.org/10.1016/j.trecan.2023.02.005
  11. J Control Release. 2023 Mar 18. pii: S0168-3659(23)00197-9. [Epub ahead of print]
    A self-amplified ferroptosis nanoagent that inhibits the tumor upstream glutathione synthesis to reverse cancer chemoresistance.
    Chuang Yang, Zheng Chen, Min Wei, Shen Hu, Mengyuan Cai, Nan Wang, Yunan Guan, Fangyuan Li, Qiang Ding, Daishun Ling.
      Ferroptosis has recently become an attractive strategy to combat the chemoresistance of cancer cells, but the intracellular ferroptosis defense system greatly challenges the efficient ferroptosis induction. Herein, we report a ferrous metal-organic framework-based nanoagent (FMN) that inhibits the intracellular upstream glutathione synthesis and induces self-amplified ferroptosis of cancer cells, for reversing chemoresistance and boosting chemotherapy. The FMN is loaded with SLC7A11 siRNA (siSLC7A11) and chemotherapeutic doxorubicin (DOX), which shows enhanced tumor cell uptake and retention, thus ensuring the effective DOX delivery and tumor intracellular iron accumulation. Importantly, the FMN simultaneously catalyzes the iron-dependent Fenton reaction and triggers the siSLC7A11-mediated suppression of upstream glutathione synthesis for intracellularly self-amplified ferroptosis, which further inhibits P-glycoprotein activity for DOX retention, and regulates the expression of Bcl-2/Bax to reverse the apoptotic resistance state of tumor cells. The FMN-mediated ferroptosis is also demonstrated in ex vivo patient-derived tumor fragment platform. Consequently, FMN successfully reverses cancer chemoresistance and achieves a highly efficient in vivo therapeutic efficacy in MCF7/ADR tumor-bearing mice. Our study provides a self-amplified ferroptosis strategy via inhibiting intracellular upstream glutathione synthesis, which is effective to reverse cancer chemoresistance.
    Keywords:  Cancer therapy; Chemoresistance; Ferroptosis; Ferrous metal-organic framework; GSH synthesis inhibition
    DOI:  https://doi.org/10.1016/j.jconrel.2023.03.030
  12. Front Oncol. 2023 ;13 1086604
    Hepatocellular carcinoma subtypes based on metabolic pathways reveals potential therapeutic targets.
    Zehua He, Qingfeng Chen, Wanrong He, Junyue Cao, Shunhan Yao, Qingqiang Huang, Yu Zheng.
       Introduction: Hepatocellular carcinoma (HCC) is an aggressive malignancy with steadily increasing incidence rates worldwide and poor therapeutic outcomes. Studies show that metabolic reprogramming plays a key role in tumor genesis and progression. In this study, we analyzed the metabolic heterogeneity of epithelial cells in the HCC and screened for potential biomarkers.
    Methods: The hepatic single-cell RNA sequencing (scRNA-seq) datasets of HCC patients and healthy controls were obtained from the Gene Expression Omnibus (GEO) database. Based on data intergration and measurement of differences among groups, the metabolic epithelial cell subpopulations were identified. The single-cell metabolic pathway was analyzed and the myeloid subpopulations were identified. Cell-cell interaction analysis and single-cell proliferation analysis were performed. The gene expression profiles of HCC patients were obtained from the GSE14520 dataset of GEO and TCGA-LIHC cohort of the UCSC Xena website. Immune analysis was performed. The differentially expressed genes (DEGs) were identified and functionally annotated. Tumor tissues from HCC patients were probed with anti-ALDOA, anti-CD68, anti-CD163, anti-CD4 and anti-FOXP3 antibodies. Results We analyzed the scRNA-seq data from 48 HCC patients and 14 healthy controls. The epithelial cells were significantly enriched in HCC patients compared to the controls (p = 0.011). The epithelial cells from HCC patients were classified into two metabolism-related subpopulations (MRSs) - pertaining to amino acid metabolism (MRS1) and glycolysis (MRS2). Depending on the abundance of these metabolic subpopulations, the HCC patients were also classified into the MRS1 and MRS2 subtype distinct prognoses and immune infiltration. The MRS2 group had significantly worse clinical outcomes and more inflamed tumor microenvironment (TME), as well as a stronger crosstalk between MRS2 cells and immune subpopulations that resulted in an immunosuppressive TME. We also detected high expression levels of ALDOA in the MRS2 cells and HCC tissues. In the clinical cohort, HCC patients with higher ALDOA expression showed greater enrichment of immunosuppressive cells including M2 macrophages and T regulatory cells.
    Discussion: The glycolytic subtype of HCC cells with high ALDOA expression is associated with an immunosuppressive TME and predicts worse clinical outcomes, providing new insights into the metabolism and prognosis of HCC.
    Keywords:  bioinformatics; hepatocellular carcinoma (HCC); metabologenomics; microenvironment; targeted therapy
    DOI:  https://doi.org/10.3389/fonc.2023.1086604
  13. Exp Gerontol. 2023 Mar 20. pii: S0531-5565(23)00075-X. [Epub ahead of print]175 112154
    Alpha-ketoglutarate as a potent regulator for lifespan and healthspan: Evidences and perspectives.
    Saghi Hakimi Naeini, Laleh Mavaddatiyan, Zahra Rashid Kalkhoran, Soroush Taherkhani, Mahmood Talkhabi.
      Aging is a natural process that determined by a functional decline in cells and tissues as organisms are growing old, resulting in an increase at risk of disease and death. To this end, many efforts have been made to control aging and increase lifespan and healthspan. These efforts have led to the discovery of several anti-aging drugs and compounds such as rapamycin and metformin. Recently, alpha-ketoglutarate (AKG) has been introduced as a potential anti-aging metabolite that can control several functions in organisms, thereby increases longevity and improves healthspan. Unlike other synthetic anti-aging drugs, AKG is one of the metabolites of the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle, and synthesized in the body. It plays a crucial role in the cell energy metabolism, amino acid/protein synthesis, epigenetic regulation, stemness and differentiation, fertility and reproductive health, and cancer cell behaviors. AKG exerts its effects through different mechanisms such as inhibiting mTOR and ATP-synthase, modulating DNA and histone demethylation and reducing ROS formation. Herein, we summarize the recent findings of AKG-related lifespan and healthspan studies and discuss AKG associated cell and molecular mechanisms involved in increasing longevity, improving reproduction, and modulating stem cells and cancer cells behavior. We also discuss the promises and limitations of AKG for delaying aging and other potential applications.
    Keywords:  ATP synthesis; Aging; Alpha-ketoglutarate; DNA methylation; Healthspan; Lifespan; mTOR
    DOI:  https://doi.org/10.1016/j.exger.2023.112154
  14. Angew Chem Int Ed Engl. 2023 Mar 19. e202301866
    Inspired by Game Theory: Glutathione-induced in Situ Michael Addition between Nanoparticles for Pyroptosis and Immunotherapy.
    Wenyao Zhen, Yang Liu, Shangjie An, Xiue Jiang.
      As its complexity and genetic instability, most tumor treatments will fail when ignoring competition and cooperation between each cancer cell and its microenvironment. Inspired by game theory, therapeutic agents can be introduced to compete for intracellular molecules to disrupt the cooperation between molecules and cells. Here, we prepare biomineralized oxidized (-)-epigallocatechin-3-o-gallate (EGCG)-molybdenum ion coordination nanoparticles for disrupting redox equilibrium and simultaneously reacting with intracellular GSH via Michael addition to form large aggregations that can mechanically disrupt endosomal and plasma membrane, stimulating pyroptosis and anti-tumor immunological responses for versatile inhibition of different types of tumors. This design disrupts the cooperation between molecules and between cancer and immune cells, gaining optimal payoff in competition and cooperation in cancer therapy.
    Keywords:  cancer therapy * pyroptosis * nanotechnology * tea polyphenols * immunotherapy
    DOI:  https://doi.org/10.1002/anie.202301866
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