bims-glucam 2024-12-22 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024–12–22
fifteen papers selected by
Sreeparna Banerjee, Middle East Technical University

A hormetic response model for glutamine stress in cancer.
Addressing Clinical Limitations of Glutaminase Inhibitors: Novel Strategies for Osimertinib-Resistant Lung Cancer by Exploiting Glutamine Metabolic Dependency.
Microenvironmental G protein-coupled estrogen receptor-mediated glutamine metabolic coupling between cancer-associated fibroblasts and triple-negative breast cancer cells governs tumour progression.
Macropinocytosis controls metabolic stress-driven CAF subtype identity in pancreatic cancer.
ATF4 promotes glutaminolysis and glycolysis in colorectal cancer by transcriptionally inducing SLC1A5.
Metabolic targeting of neuroblastoma, an update.
Momordicine-I suppresses head and neck cancer growth by modulating key metabolic pathways.
Immunometabolism in head and neck squamous cell carcinoma: Hope and challenge.
myCAF-derived exosomal PWAR6 accelerates CRC liver metastasis via altering glutamine availability and NK cell function in the tumor microenvironment.
Deuterium Metabolic Imaging Enables the Tracing of Substrate Fluxes Through the Tricarboxylic Acid Cycle in the Liver.
Current status of serum metabolites biomarkers for polyps and colorectal cancer: a systematic review.
A turn-on mitochondria-targeted iridium (Ⅲ) Complex-Based probe for glutathione detection and photodynamic therapy of cancer cells.
Inhibition of glutaminase elicits senolysis in therapy-induced senescent melanoma cells.
Senolysis by GLS1 Inhibition Ameliorates Kidney Aging by Inducing Excessive mPTP Opening through MFN1.
Editorial: Unraveling the complex interplay between aging, immunity, metabolites, and metabolism in endocrine-related cancers.

Trends Cancer. 2024 Dec 16. pii: S2405-8033(24)00274-7. [Epub ahead of print]

A hormetic response model for glutamine stress in cancer.

Shea F Grenier, Cosimo Commisso.

  Glutamine metabolism supports the development and progression of many cancers and is considered a therapeutic target. Attempts to inhibit glutamine metabolism have resulted in limited success and have not translated into clinical benefit. The outcomes of these clinical studies, along with preclinical investigations, suggest that cellular stress responses to glutamine deprivation or targeting may be modeled as a biphasic hormetic response. By recognizing the multifaceted aspects of glutamine metabolism inhibition within a more comprehensive biological framework, the adoption of this model may guide future fundamental and translational studies. To achieve clinical efficacy, we posit that as a field we will need to anticipate the hormetic effects of glutamine stress and consider how best to co-target cancer cell adaptive mechanisms.

Keywords:  cancer; glutamine stress; hormesis; metabolism; targeted therapies; therapeutics

DOI:  https://doi.org/10.1016/j.trecan.2024.11.008
Adv Sci (Weinh). 2024 Dec 16. e2411479

Addressing Clinical Limitations of Glutaminase Inhibitors: Novel Strategies for Osimertinib-Resistant Lung Cancer by Exploiting Glutamine Metabolic Dependency.

Jiali Huang, Xiankang Zhang, Hui Zhang, Yu Li, Huidan Huang, Zhiyu Li, Zhixia Qiu, Hongxi Wu, Dechun Huang, Xi Xu, Jinlei Bian.

  Overcoming acquired resistance to Osimertinib remains a critical challenge in treating NSCLC. This research indicates that Osimertinib-resistant cells exhibit a strong dependence on glutamine metabolism. However, targeting GLS1 shows limited anticancer effects, probably because it cannot fully block the glutamine metabolic pathway. The investigation reveals that a more effective strategy involves simultaneously inhibiting both ASCT2 and GLS1. After confirming the efficacy of this dual-targeting approach against Osimertinib-resistant cells in preclinical models, the potential of utilizing a broad-spectrum glutamine metabolism antagonist is further explored to achieve superior antitumor efficacy. DON, broad-spectrum glutamine antagonist, presents toxicity issues. Herein, the high NQO1 expression in Osimertinib-resistant NSCLC cells is leveraged to design an NQO1-responsive DON prodrug, 10e (LBJ-10e). This prodrug demonstrates superior safety compared to natural DON and greater antitumor activity against resistant tumors compared to the clinical phase II drug DRP104. These findings may address the clinical limitations of GLS1 allosteric inhibitors and underscore prodrug strategies in effectively treating Osimertinib-resistant lung cancer, providing a foundation for future clinical trials.

Keywords:  NQO1; NSCLC; Osimertinib resistance; drug design; glutamine

DOI:  https://doi.org/10.1002/advs.202411479
Clin Transl Med. 2024 Dec;14(12): e70131

Microenvironmental G protein-coupled estrogen receptor-mediated glutamine metabolic coupling between cancer-associated fibroblasts and triple-negative breast cancer cells governs tumour progression.

Chongwu He, Meixi Peng, Xiaoqiang Zeng, Hanzhi Dong, Zhengkui Sun, Jiawei Xu, Manran Liu, Liyan Liu, Yanxiao Huang, Zhiqiang Peng, Yu-An Qiu, Chunling Jiang, Bin Xu, Tenghua Yu.

   BACKGROUND: Triple-negative breast cancer (TNBC) is a particularly aggressive type of breast cancer, known for its lack of effective treatments and unfavorable prognosis. The G protein-coupled estrogen receptor (GPER), a novel estrogen receptor, is linked to increased malignancy in various cancers. However, its involvement in the metabolic regulation of cancer-associated fibroblasts (CAFs), a key component in the tumour microenvironment, remains largely unexplored. This study investigates how GPER influences the metabolic interaction between CAFs and TNBC cells, aiming to identify potential therapeutic targets.
METHODS: The co-culture system is performed to examine the interaction between CAFs and TNBC cells, with a focus on GPER-mediated glutamine production and release by CAFs and its subsequent uptake and utilization by TNBC cells. The definite roles of microenvironmental GPER/cAMP/PKA/CREB signalling in regulating the expression of glutamine synthetase (GLUL) and lactate dehydrogenase B (LDHB) are further investigated.
RESULTS: Our findings reveal that estrogen-activated GPER in CAFs significantly upregulates the expression of GLUL and LDHB, leading to increased glutamine production. This glutamine is then secreted into the extracellular matrix and absorbed by TNBC cells, enhancing their viability, motility, and chemoresistance both in vitro and in vivo. TNBC cells further metabolize the glutamine through the glutamine transporter (ASCT2) and glutaminase (GLS1) axes, which, in turn, promote mitochondrial activity and tumour progression.
CONCLUSIONS: The study identifies GPER as a critical mediator of metabolic coupling between CAFs and TNBC cells, primarily through glutamine metabolism. Targeting the estrogen/GPER/glutamine signalling axis in CAFs offers a promising therapeutic strategy to inhibit TNBC progression and improve patient outcomes. This novel insight into the tumour microenvironment highlights the potential of metabolic interventions in treating TNBC.
KEY POINTS: Estrogen-activated GPER in CAFs enhances GLUL and LDHB expression via the cAMP/PKA/CREB signalling, facilitating glutamine production and utilization. Microenvironmental GPER-induced glutamine serves as a crucial mediator of metabolic coupling between CAFs and TNBC cells, boosting tumour progression by enhancing mitochondrial function. Targeting the glutamine metabolic coupling triggered by estrogen/GPER/GLUL signalling in CAFs is a promising therapeutic strategy for TNBC treatment.

Keywords:  CAFs; GPER; TNBC; glutamine metabolism; tumour progression

DOI:  https://doi.org/10.1002/ctm2.70131
bioRxiv. 2024 Dec 05. pii: 2024.11.29.625709. [Epub ahead of print]

Macropinocytosis controls metabolic stress-driven CAF subtype identity in pancreatic cancer.

Yijuan Zhang, Li Ling, Swetha Maganti, Jennifer L Hope, Cheska Marie Galapate, Florent Carrette, Karen Duong-Polk, Anindya Bagchi, David A Scott, Andrew M Lowy, Linda M Bradley, Cosimo Commisso.

  Pancreatic ductal adenocarcinoma (PDAC) tumors are deficient in glutamine, an amino acid that tumor cells and CAFs use to sustain their fitness. In PDAC, both cell types stimulate macropinocytosis as an adaptive response to glutamine depletion. CAFs play a critical role in sculpting the tumor microenvironment, yet how adaptations to metabolic stress impact the stromal architecture remains elusive. In this study, we find that macropinocytosis functions to control CAF subtype identity when glutamine is limiting. Our data demonstrate that metabolic stress leads to an intrinsic inflammatory CAF (iCAF) program driven by MEK/ERK signaling. Utilizing in vivo models, we find that blocking macropinocytosis alters CAF subtypes and reorganizes the tumor stroma. Importantly, these changes in stromal architecture can be exploited to sensitize PDAC to immunotherapy and chemotherapy. Our findings demonstrate that metabolic stress plays a role in shaping the tumor microenvironment, and that this attribute can be harnessed for therapeutic impact.

Keywords:  CAF heterogeneity; Metabolic stress; drug delivery; macropinocytosis; pancreatic cancer; stromal architecture; tumor microenvironment

DOI:  https://doi.org/10.1101/2024.11.29.625709
Acta Biochim Biophys Sin (Shanghai). 2024 Dec 18.

ATF4 promotes glutaminolysis and glycolysis in colorectal cancer by transcriptionally inducing SLC1A5.

Zengli Zhou, Shufang Ye, Jingyu Chen, Fei Dai, Luyi Chen, Ran Ye, Jianmei Zhang, Gefei Chen, Yanjiao Wang, Yangyang Liu.

  Glutaminolysis and glycolysis promote the malignant progression of colorectal cancer. The role of activating transcription factor 4 (ATF4) in solute carrier family 1 member 5 (SLC1A5)-mediated glutaminolysis and glycolysis remains to be elucidated. SLC1A5 and ATF4 expression levels are detected in colorectal cancer tissues. ATF4 is knocked down or overexpressed to assess its role in cell viability, migration and invasion. SLC1A5 is knocked down to evaluate its role in cell viability, migration, invasion, and metastasis and the metabolism of glutamine and glucose. The regulatory effect of the transcription factor ATF4 on SLC1A5 transcription and expression is determined using a luciferase reporter assay and chromatin immunoprecipitation (ChIP) techniques. Upregulated ATF4 and SLC1A5 expressions are observed in tumor tissue, which is positively correlated with the tumor, node, and metastasis (TNM) stages. ATF4-overexpressing SW480 cells show the increased cell viability, migration and invasion. Conversely, ATF4 knockdown decreases the viability, migration and invasion of HCT-116 cells. SLC1A5 knockdown inhibits viability, migration, invasion, and metastasis and the metabolism of glutamine and glucose in HT-29 cells, as well as the expressions of two key glycolytic enzymes, hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2). The luciferase activity of the SLC1A5 promoter is increased by ATF4 overexpression. SLC1A5 promoter enrichment is increased by anti-ATF4 antibody immunoprecipitation in ATF4-overexpressing colorectal cells, indicating that ATF4 targets SLC1A5 to promote glutamine and glucose metabolism in these cells. In summary, the ATF4/SLC1A5 axis plays a significant role in the progression of colorectal cancer by regulating glutamine metabolism and glycolysis.

Keywords:  ATF4; SLC1A5; colorectal cancer; glycolysis

DOI:  https://doi.org/10.3724/abbs.2024226
Cancer Lett. 2024 Dec 14. pii: S0304-3835(24)00788-2. [Epub ahead of print] 217393

Metabolic targeting of neuroblastoma, an update.

Leila Jahangiri.

  Neuroblastoma is a paediatric cancer of the sympathetic nervous system that originates from the neural crest and can be categorised into stages and risk groups. Risk groups inform treatment options and high-risk cases bear a 50% probability of relapse post-treatment remission. In neuroblastoma, MYCN amplification is the strongest predictor of unfavourable patient prognosis; circa 50% of high-risk cases display MYCN amplification. This dismal prognosis is perhaps influenced by the MYCN-driven metabolic rewiring of these cells since the MYC family is indicated in the regulation of proliferation, cell death, metabolism, differentiation, and protein synthesis. This review aims to capture the most recent studies that investigate metabolic rewiring in MYCN-amplified and MYCN-activated cells from the perspective of alterations to glycolysis, the TCA cycle, and oxidative phosphorylation, in addition to changes to amino acid, nucleotide, and lipid metabolism that can be relevant to therapy. A better understanding of the metabolic profile of MYCN-amplified disease will facilitate the identification of effective treatment options and improve the prognosis of high-risk neuroblastoma patients.

Keywords:  MYCN amplification; Neuroblastoma; metabolism; therapy

DOI:  https://doi.org/10.1016/j.canlet.2024.217393
Cell Commun Signal. 2024 Dec 18. 22(1): 597

Momordicine-I suppresses head and neck cancer growth by modulating key metabolic pathways.

Debojyoty Bandyopadhyay, Ellen T Tran, Ruchi A Patel, Matthew A Luetzen, Kevin Cho, Leah P Shriver, Gary J Patti, Mark A Varvares, David A Ford, Kyle S McCommis, Ratna B Ray.

  One of the hallmarks of cancer is metabolic reprogramming which controls cellular homeostasis and therapy resistance. Here, we investigated the effect of momordicine-I (M-I), a key bioactive compound from Momordica charantia (bitter melon), on metabolic pathways in human head and neck cancer (HNC) cells and a mouse HNC tumorigenicity model. We found that M-I treatment on HNC cells significantly reduced the expression of key glycolytic molecules, SLC2A1 (GLUT-1), HK1, PFKP, PDK3, PKM, and LDHA at the mRNA and protein levels. We further observed reduced lactate accumulation, suggesting glycolysis was perturbed in M-I treated HNC cells. Metabolomic analyses confirmed a marked reduction in glycolytic and TCA cycle metabolites in M-I-treated cells. M-I treatment significantly downregulated mRNA and protein expression of essential enzymes involved in de novo lipogenesis, including ACLY, ACC1, FASN, SREBP1, and SCD1. Using shotgun lipidomics, we found a significant increase in lysophosphatidylcholine and phosphatidylcholine loss in M-I treated cells. Subsequently, we observed dysregulation of mitochondrial membrane potential and significant reduction of mitochondrial oxygen consumption after M-I treatment. We further observed M-I treatment induced autophagy, activated AMPK and inhibited mTOR and Akt signaling pathways and leading to apoptosis. However, blocking autophagy did not rescue the M-I-mediated alterations in lipogenesis, suggesting an independent mechanism of action. M-I treated mouse HNC MOC2 cell tumors displayed reduced Hk1, Pdk3, Fasn, and Acly expression. In conclusion, our study revealed that M-I inhibits glycolysis, lipid metabolism, induces autophagy in HNC cells and reduces tumor volume in mice. Therefore, M-I-mediated metabolic reprogramming of HNC has the potential for important therapeutic implications.

Keywords:  Autophagy; Glycolysis; Head and neck cancer; Lipid metabolism; Metabolites; Momordicine-I

DOI:  https://doi.org/10.1186/s12964-024-01951-w
Biochim Biophys Acta Mol Basis Dis. 2024 Dec 15. pii: S0925-4439(24)00623-9. [Epub ahead of print]1871(3): 167629

Immunometabolism in head and neck squamous cell carcinoma: Hope and challenge.

Yi-Jia-Ning Zhang, Yao Xiao, Zi-Zhan Li, Lin-Lin Bu.

  Immunotherapy has improved the survival rate of patients with head and neck squamous cell carcinoma (HNSCC), but less than 20 % of them have a durable response to these treatments. Excessive local recurrence and lymph node metastasis ultimately lead to death, making the 5-year survival rate of HNSCC still not optimistic. Cell metabolism has become a key determinant of the viability and function of cancer cells and immune cells. In order to maintain the enormous anabolic demand, tumor cells choose a specialized metabolism different from non-transformed somatic cells, leading to changes in the tumor microenvironment (TME). In recent years, our understanding of immune cell metabolism and cancer cell metabolism has gradually increased, and we have begun to explore the interaction between cancer cell metabolism and immune cell metabolism in a way which is meaningful for treatment. Understanding the different metabolic requirements of different cells that constitute the immune response to HNSCC is beneficial for revealing metabolic heterogeneity and plasticity, thereby enhancing the effect of immunotherapy. In this review, we have concluded that the relevant metabolic processes that affect the function of immune cells in HNSCC TME and proposed our own opinions and prospects on how to use metabolic intervention to enhance anti-tumor immune responses.

Keywords:  Head and neck squamous cell carcinoma; Immunometabolism; Immunotherapy; Prognosis

DOI:  https://doi.org/10.1016/j.bbadis.2024.167629
J Hematol Oncol. 2024 Dec 18. 17(1): 126

myCAF-derived exosomal PWAR6 accelerates CRC liver metastasis via altering glutamine availability and NK cell function in the tumor microenvironment.

Hongsheng Fang, Weixing Dai, Ruiqi Gu, Yanbo Zhang, Jin Li, Wenqin Luo, Shanyou Tong, Lingyu Han, Yichao Wang, Chengyao Jiang, Xue Wang, Renjie Wang, Guoxiang Cai.

BACKGROUND: Liver metastasis from colorectal cancer (CRC) is a major clinical challenge that severely affects patient survival. myofibroblastic cancer-associated fibroblasts (myCAFs) are a major component of the CRC tumor microenvironment, where they contribute to tumor progression and metastasis through exosomes.
METHODS: Single-cell analysis highlighted a notable increase in myCAFs in colorectal cancer liver metastases (CRLM). Exosomal sequencing identified PWAR6 as the most significantly elevated lncRNA in these metastatic tissues. In vivo and in vitro assays confirmed PWAR6's roles in CRC cell stemness, migration, and glutamine uptake. RNA pulldown, RIP, and Co-IP assays investigated the molecular mechanisms of the PWAR6/NRF2/SLC38A2 signaling axis in CRC progression, flow cytometry was used to assess NK cell activity and cytotoxicity.
RESULTS: Clinically, higher PWAR6 expression levels are strongly associated with increased 68Ga FAPI-PET/CT SUVmax values, particularly in CRLM patients, where expression significantly exceeds that of non-LM cases and normal colon tissues. Regression analysis and survival data further support PWAR6 as a negative prognostic marker, with elevated levels correlating with worse patient outcomes. Mechanistically, PWAR6 promotes immune evasion by inhibiting NRF2 degradation through competitive binding with Keap1, thereby upregulating SLC38A2 expression, which enhances glutamine uptake in CRC cells and depletes glutamine availability for NK cells.
CONCLUSION: myCAFs derived exosomes PWAR6 represents a pivotal marker for CRC liver metastasis, and its targeted inhibition with ASO-PWAR6, in combination with FAPI treatment, effectively curtails metastasis in preclinical models, offering promising therapeutic potential for clinical management.

DOI: https://doi.org/10.1186/s13045-024-01643-5
NMR Biomed. 2025 Jan;38(1): e5309

Deuterium Metabolic Imaging Enables the Tracing of Substrate Fluxes Through the Tricarboxylic Acid Cycle in the Liver.

Viktoria Ehret, Sabine C Dürr, Usevalad Ustsinau, Joachim Friske, Thomas Scherer, Clemens Fürnsinn, Jana Starčuková, Thomas H Helbich, Cécile Philippe, Martin Krššák.

  Alterations in tricarboxylic acid (TCA) cycle metabolism are associated with hepatic metabolic disorders. Elevated hepatic acetate concentrations, often attributed to high caloric intake, are recognized as a pivotal factor in the etiology of obesity and metabolic syndrome. Therefore, the assessment of acetate breakdown and TCA cycle activity plays a central role in understanding the impact of diet-induced alterations on liver metabolism. Magnetic resonance-based deuterium metabolic imaging (DMI) could help to unravel the underlying mechanisms involved in disease development and progression, however, the application of conventional deuterated glucose does not lead to substantial enrichment in hepatic glutamine and glutamate. This study aimed to demonstrate the feasibility of DMI for tracking deuterated acetate breakdown via the TCA cycle in lean and diet-induced fatty liver (FL) rats using 3D DMI after an intraperitoneal infusion of sodium acetate-d3 at 9.4T. Localized and nonlocalized liver spectra acquired at 10 time points post-injection over a 130-min study revealed similar intrahepatic acetate uptake in both animal groups (AUCFL = 717.9 ± 131.1 mM▯min-1, AUClean = 605.1 ± 119.9 mM▯min-1, p = 0.62). Metabolic breakdown could be observed in both groups with an emerging glutamine/glutamate (Glx) peak as a downstream metabolic product (AUCFL = 113.6 ± 23.8 mM▯min-1, AUClean = 136.7 ± 41.7 mM▯min-1, p = 0.68). This study showed the viability of DMI for tracking substrate flux through the TCA cycle, underscoring its methodological potential for imaging metabolic processes in the body.

Keywords:  MASLD; TCA cycle; acetate; deuterium metabolic imaging; fatty liver disease; metabolism

DOI:  https://doi.org/10.1002/nbm.5309
Gastroenterol Rep (Oxf). 2024 ;12 goae106

Current status of serum metabolites biomarkers for polyps and colorectal cancer: a systematic review.

Maryam Fatimah Abu Bakar, Azmawati Mohammed Nawi, Siok Fong Chin, Suzana Makpol.

   Background: Early detection of colorectal cancer (CRC) is crucial to enhance the disease treatment and prognosis of patients. Colonoscopy remains the gold standard for CRC detection; however, it requires trained personnel with expensive tools. Currently, serum metabolites have been discovered to be used to discriminate patients with polyps and CRC. This study aimed to identify the most commonly detected predictive serum metabolites for polyps and CRC.
Methods: A systematic search of the Web of Science, PubMed, and Cochrane Library databases was conducted using PRISMA guidelines. Ten studies investigating serum metabolite biomarkers of CRC and polyps using different analytical platforms and study populations were included. QUADOMICS tool was used to analyse the quality of the included studies. All reported metabolites were then enriched into the pathways using MetaboAnalyst 5.0.
Results: We found that several potential signature metabolites overlapped between studies, including tyrosine, lysine, cystine, arabinose, and lactate for CRC and lactate and glutamate for polyps. The most affected pathways related to CRC were the urea cycle, glutathione metabolism, purine metabolism, glutamate metabolism, and ammonia recycling. In contrast, those affected in the polyps were the urea cycle, glutamate metabolism, glutathione metabolism, arginine and proline metabolism, and carnitine synthesis.
Conclusions: This review has found commonly detected serum metabolites for polyps and CRC with huge potential to be used in clinical settings. However, the differences between altered pathways in polyps and CRC, other external factors, and their effects on the regulation level, sensitivity, and specificity of each identified metabolite remained unclear, which could benefit from a further extensive cohort study and well-defined analysis equipment.

Keywords:  colorectal adenoma; colorectal carcinoma; metabolomics; screening tool; serum biomarker

DOI:  https://doi.org/10.1093/gastro/goae106
Spectrochim Acta A Mol Biomol Spectrosc. 2024 Dec 11. pii: S1386-1425(24)01745-1. [Epub ahead of print]329 125579

A turn-on mitochondria-targeted iridium (Ⅲ) Complex-Based probe for glutathione detection and photodynamic therapy of cancer cells.

Xueting Mao, Xiao Fei, Tangxuan Cai, Sha Xu, Daobin Zhang, Shouzhi Pu, Zhijian Li.

  As one of the most abundant biothiols in cells, glutathione (GSH) usually exists in a dynamic equilibrium of oxidized glutathione (GSSG) and reduces glutathione redox, and plays an essential reducing substance to maintain the REDOX balance of the microenvironment. So, the development of a reliable GSH sensor will be important for living cells and organisms. We fabricated a mitochondria targeted "turn-on" fluorescent sensor based on Ir (III) complex and successfully detected endogenous and exogenous GSH in living cells and zebrafish. For the probe Ir-DINI, a robust electron-withdrawing group 2,4-dinitrobenzoyl was introduced to quench the fluorescence, which could be broken through electrostatic interaction with GSH, following exposing a strong fluorescent Ir (Ⅲ) complex Ir-OH. On the other hand, photodynamic therapy (PDT) has attracted much attention in recent years due to its minimally invasive treatment. We found that singlet oxygen yields of probe Ir-DINI displayed an enhancement before and after the detection of GSH. Additionally, photodynamic studies in living cells illustrated that after reacting with GSH, probe Ir-DINI exhibited more obvious phototoxicity than before the detection of GSH. So the probe Ir-DINI could be served as a GSH sensor and potential GSH-activated photosensitizer for photodynamic therapy.

Keywords:  Bioimaging; Fluorescent probe; Glutathione; Iridium complex; Single-linear oxygen

DOI:  https://doi.org/10.1016/j.saa.2024.125579
Cell Death Dis. 2024 Dec 18. 15(12): 902

Inhibition of glutaminase elicits senolysis in therapy-induced senescent melanoma cells.

Justin Kim, Bryce Brunetti, Ayanesh Kumar, Ankit Mangla, Kord Honda, Akihiro Yoshida.

The cyclin D1-Cyclin-Dependent Kinases 4 and 6 (CDK4/6) complex is crucial for the development of melanoma. We previously demonstrated that targeting CDK4/6 using small molecule inhibitors (CDK4/6i) suppresses BrafV600E melanoma growth in vitro and in vivo through induction of cellular senescence. However, clinical trials investigating CDK4/6i in melanoma have not yielded successful outcomes, underscoring the necessity to enhance the therapeutic efficacy of CDK4/6i. Accumulated research has shown that while senescence initially suppresses cell proliferation, a prolonged state of senescence eventually leads to tumor relapse by altering the tumor microenvironment, suggesting that removal of those senescent cells (in a process referred to as senolysis) is of clinical necessity to facilitate clinical response. We demonstrate that glutaminase 1 (GLS1) expression is specifically upregulated in CDK4/6i-induced senescent BrafV600E melanoma cells. Upregulated GLS1 expression renders BrafV600E melanoma senescent cells vulnerable to GLS1 inhibitor (GLS1i). Furthermore, we demonstrate that this senolytic approach targeting upregulated GLS1 expression is applicable even though those cells developed resistance to the BrafV600E inhibitor vemurafenib, a frequently encountered substantial clinical challenge to treating patients. Thus, this novel senolytic approach may revolutionize current CDK4/6i mediated melanoma treatment if melanoma cells undergo senescence prior to developing resistance to CDK4/6i. Given that we demonstrate that a low dose of vemurafenib induced senescence, which renders BrafV600E melanoma cells susceptible to GLS1i and recent accumulated research shows many cancer cells undergo senescence in response to chemotherapy, radiation, and immunotherapy, this senolytic therapy approach may prove applicable to a wide range of cancer types once senescence and GLS1 expression are induced.

DOI: https://doi.org/10.1038/s41419-024-07284-3
J Gerontol A Biol Sci Med Sci. 2024 Dec 19. pii: glae294. [Epub ahead of print]

Senolysis by GLS1 Inhibition Ameliorates Kidney Aging by Inducing Excessive mPTP Opening through MFN1.

Yuting Chen, Nan Zhao, Yu Zhang, Xueqi Chen, Yi Chen, Yifan Wang, Jianqing Wu, Weihong Zhao.

  Cellular senescence is a pivotal contributor to aging and age-related diseases. The targeted elimination of senescent cells, known as senolysis, has emerged as a promising therapeutic strategy for mitigating these conditions. Glutaminase 1 (GLS1), a key enzyme in the glutaminolysis pathway, has been implicated in various cellular senescence processes. However, its specific role in senescent renal tubular epithelial cells (TECs) remains unclear. This study investigates the role and underlying mechanisms of GLS1 in senescent TECs. Using D-galactose (D-gal)-induced senescence of HK-2 cells, we found that GLS1 inhibition eliminated senescent TECs by promoting excessive mitochondrial permeability transition pore (mPTP) opening. Mechanistically, the excessive mPTP opening is associated with upregulation of mitofusin 1 (MFN1). Inhibition of GLS1 in D-gal-treated HK-2 cells induced a shift in mitochondrial dynamics from fission to fusion, accompanied by a significant increase in MFN1 expression. Knocking down MFN1 reduced the mPTP opening and the expression of mPTP-related genes (PPIF, VDAC and BAX) in cells co-treated with D-gal and the GLS1 inhibitor BPTES. Moreover, treatment of aged mice with BPTES specifically eliminated senescent TECs and ameliorated age-associated kidney disease. These findings reveal that GLS1 inhibition eliminate senescent TECs by promoting excessive mPTP opening, suggesting that targeting GLS1 may be a novel senolytic strategy for alleviating aging-related kidney diseases.

Keywords:  GLS1; MFN1; kidney aging; mPTP; senolysis

DOI:  https://doi.org/10.1093/gerona/glae294
Front Endocrinol (Lausanne). 2024 ;15 1527867

Editorial: Unraveling the complex interplay between aging, immunity, metabolites, and metabolism in endocrine-related cancers.

Guang-Liang Chen, Yubin Luo, Yuwei Zhang, Chao Liu.



Keywords:  Mendelian randomization; aging; breast cancer; endocrine-related cancers; immune; metabolic

DOI:  https://doi.org/10.3389/fendo.2024.1527867