Cancer & Metabolism最新文献

{"title":"TRIM22 governs tumorigenesis and protects against endometrial cancer-associated cachexia by inhibiting inflammatory response and adipose thermogenic activity.","authors":"Liping Zhang, Quanrong Li, Meiting Wu, Xiushan Feng, Weichao Dai, Peifang Chen, Dezhao Chen, Zhiqun Zheng, Xiaoyan Lin, Gang Wei","doi":"10.1186/s40170-025-00386-2","DOIUrl":"https://doi.org/10.1186/s40170-025-00386-2","url":null,"abstract":"<p><strong>Background: </strong>Endometrial cancer (EC) is one of the most common cancers in women, with a short overall survival and poor prognosis. Besides the biologically aggressive EC properties, Cancer-associated cachexia is the main factor. However, the detailed mechanism underlying EC-related cachexia and its harmful effects on EC progression and patient prognosis remains unclear.</p><p><strong>Methods: </strong>For clinical specimen and the vitro experiment, we detected TRIM22 expression level, EC patients' survival time, EC cell functional change, and adipose thermogenic changes to identify the function of TRIM22 in EC progression, EC-associated cachexia, and their molecular mechanisms. Then, for the vivo experiment, we exploited the xenografts in mice to identify the function of TRIM22 again, and to screen the drug therapeutic schedule.</p><p><strong>Results: </strong>Herein, we demonstrated that TRIM22 inhibited EC cell growth, invasion, and migration. Interleukin (IL)-6 mediated brown adipose tissue activation and white adipose tissue browning which induced EC-related cachexia. TRIM22 suppressed the EC cells' secretion of IL-6, and IL-6 mediated EC-related cachexia. Mechanistically, TRIM22 inhibited EC progression by suppressing the nucleotide-binding oligomerization domain 2(NOD2)/nuclear factor-kappaB (NF-κB) signaling pathway, with the purpose of impeding the production of IL-6. Moreover, we revealed that TRIM22 inhibited EC-associated cachexia by suppressing the IL-6/IL-6 receptor (IL-6R) signaling pathway. Therapeutically, we demonstrated that combination treatment with a TRIM22 inducer (progesterone) and a thermogenic inhibitor (IL-6R antibody) synergistically augmented the antitumor efficacy of carbotaxol (carboplatin and paclitaxel), in vivo.</p><p><strong>Conclusion: </strong>Our data reveals that TRIM22-EC-IL-6-cachexia cross-communication has important clinical relevance and that the use of combined therapy holds great promise for enhancing the efficacy of anti-ECs. (Fig. graphical abstract).</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"17"},"PeriodicalIF":6.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the powerhouse: ASCL1-driven small cell lung cancer is characterized by higher numbers of mitochondria and enhanced oxidative phosphorylation.","authors":"Anna Solta, Büsra Ernhofer, Kristiina Boettiger, Christian Lang, Zsolt Megyesfalvi, Theresa Mendrina, Dominik Kirchhofer, Gerald Timelthaler, Beata Szeitz, Melinda Rezeli, Clemens Aigner, Arvand Haschemi, Lukas W Unger, Balazs Dome, Karin Schelch","doi":"10.1186/s40170-025-00382-6","DOIUrl":"10.1186/s40170-025-00382-6","url":null,"abstract":"<p><strong>Background: </strong>Small cell lung cancer (SCLC) is an aggressive malignancy with distinct molecular subtypes defined by transcription factors and inflammatory characteristics. This follow-up study aimed to validate the unique metabolic phenotype in achaete-scute homologue 1 (ASCL1)-driven SCLC cell lines and human tumor tissue.</p><p><strong>Methods: </strong>Metabolic alterations were analyzed using proteomic data. Structural and functional differences of mitochondria were investigated using qPCR, flow cytometry, confocal imaging, and transmission electron microscopy and seahorse assays. Several metabolic inhibitors were tested using MTT-based and clonogenic assays. Single-cell enzyme activity assays were conducted on cell lines and tumor tissue samples of SCLC patients.</p><p><strong>Results: </strong>We found increased mitochondrial numbers correlating with higher oxidative phosphorylation activity in ASCL1-dominant cells compared to other SCLC subtypes. Metabolic inhibitors targeting mitochondrial respiratory complex-I or carnitine palmitoyltransferase 1 revealed higher responsiveness in SCLC-A. Conversely, we demonstrated that non-ASCL1-driven SCLCs with lower oxidative signatures show dependence on glutaminolysis as evidenced by the enhanced susceptibility to glutaminase inhibition. Accordingly, we detected increased glutamate-dehydrogenase activity in non-ASCL1-dominant cell lines as well as in human SCLC tissue samples.</p><p><strong>Conclusions: </strong>Distinct SCLC subtypes exhibit unique metabolic vulnerabilities, suggesting potential for subtype-specific therapies targeting the respiratory chain, fatty acid transport, or glutaminolysis.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"16"},"PeriodicalIF":6.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunogenic shift of arginine metabolism triggers systemic metabolic and immunological reprogramming to suppress HER2 + breast cancer.","authors":"Vandana Sharma, Veani Fernando, Xunzhen Zheng, Eun-Seok Choi, Osama Sweef, Venetia Thomas, Justin Szpendyk, Saori Furuta","doi":"10.1186/s40170-025-00384-4","DOIUrl":"10.1186/s40170-025-00384-4","url":null,"abstract":"<p><strong>Background: </strong>Arginine metabolism in tumors is often shunted into the pathway producing pro-tumor and immune suppressive polyamines (PAs), while downmodulating the alternative nitric oxide (NO) synthesis pathway. Aiming to correct arginine metabolism in tumors, arginine deprivation therapy and inhibitors of PA synthesis have been developed. Despite some therapeutic advantages, these approaches have often yielded severe side effects, making it necessary to explore an alternative strategy. We previously reported that supplementing sepiapterin (SEP), the endogenous precursor of tetrahydrobiopterin (BH_4, the essential NO synthase cofactor), could correct arginine metabolism in tumor cells and tumor-associated macrophages (TAMs) and induce their metabolic and phenotypic reprogramming. We saw that oral SEP treatment effectively suppressed the growth of HER2-positive mammary tumors in animals. SEP also has no reported dose-dependent toxicity in clinical trials for metabolic disorders. In the present study, we tested our hypothesis that a long-term administration of SEP to individuals susceptible to HER2-positive mammary tumor would protect them against tumor occurrence.</p><p><strong>Methods: </strong>We administered SEP, in comparison to control DMSO, to MMTV-neu mice susceptible to HER2-positive mammary tumors for 8 months starting at their pre-pubertal stage. We monitored tumor onsets to determine the rate of tumor-free survival. After 8 months of treatment, we grouped animals into DMSO treatment with or without tumors and SEP treatment with or without tumors. We analyzed blood metabolites, PBMC, and bone marrow of DMSO vs. SEP treated animals.</p><p><strong>Results: </strong>We found that a long-term use of SEP in animals susceptible to HER2-positive mammary tumors effectively suppressed tumor occurrence. These SEP-treated animals had undergone reprogramming of the systemic metabolism and immunity, elevating total T cell counts in the circulation and bone marrow. Given that bone marrow-resident T cells are mostly memory T cells, it is plausible that chronic SEP treatment promoted memory T cell formation, leading to a potent tumor prevention.</p><p><strong>Conclusions: </strong>These findings suggest the possible roles of the SEP/BH₄/NO axis in promoting memory T cell formation and its potential therapeutic utility for preventing HER2-positive breast cancer.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"15"},"PeriodicalIF":6.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WTAP contributes to platinum resistance in high-grade serous ovarian cancer by up-regulating malic acid: insights from liquid chromatography and mass spectrometry analysis.","authors":"Ming Wang, Shuiqing Xu, Jianqing Xu, Jiahui Wei, Yumei Wu","doi":"10.1186/s40170-025-00383-5","DOIUrl":"10.1186/s40170-025-00383-5","url":null,"abstract":"<p><p>High-grade serous cancer (HGSC) is the most prevalent and aggressive subtype of ovarian cancer. In this study, we utilized liquid chromatography and mass spectrometry analysis to investigate metabolic alterations in HGSC. Among the 1353 metabolites identified, 140 were significantly differed between HGSC and normal ovarian tissue. KEGG pathway enrichment analysis revealed 23 distinct metabolic pathways, including the alanine/aspartate/glutamate metabolism, pyruvate metabolism, biosynthesis of amino acids, and citrate cycle, etc. Of the significantly differentiated metabolites, malic acid, fumarate, and phosphoenolpyruvate were found in the citrate cycle and glycolysis. In further analysis, 22 differentially expressed genes (DEGs) of glucose metabolism were found between HGSC and normal controls. Multivariate Cox analysis of the 22 DEGs showed that ME1, ALDOC, and RANBP2 were associated with overall survival in the TCGA cohort.Bioinformatic analysis indicated WTAP is strongly correlated to the expression of ME1, which is a rate-limiting enzyme that regulates the shuttle of malic acid in mitochondria and cytoplasm. After the knockdown of WTAP in A2780 and OVCAR-3 cells, the activity of the malic enzyme decreased which led to the accumulation of malic acid and citric acid, and the reduction of pyruvate and lactic acid. In A2780 and OVCAR-3 cells, the IC50 to platinum was increased after the knockdown of WTAP. After the knockdown of WTAP, the expression of ME1 was down-regulated and the m6A modification was down-regulated in ovarian cell lines. On the SRAMP website, there were two binding sites with high m6A scores at the 5 '-UTR 177 and 970 of ME1 mRNA. WTAP contributes to the platinum resistance through regulating the conversion from aerobic glycolysis to OXPHOS by upregulating the expression of ME1.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"14"},"PeriodicalIF":6.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11916999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: STEAP4 inhibits cisplatin-induced chemotherapy resistance through suppressing PI3K/AKT in hepatocellular carcinoma.","authors":"Binhui Xie, Baiyin Zhong, Zhenxian Zhao, Jie Hu, Jianqiong Yang, Yuankang Xie, Jianhong Zhang, Jianting Long, Xuewei Yang, Heping Li","doi":"10.1186/s40170-024-00356-0","DOIUrl":"10.1186/s40170-024-00356-0","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"13"},"PeriodicalIF":6.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11892191/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Obesity and overweight in R/R DLBCL patients is associated with a better response to treatment of R2-GDP-GOTEL trial. Potential role of NK CD8 + cells and vitamin D.","authors":"Lourdes Hontecillas-Prieto, Daniel J García-Domínguez, Carlos Jiménez-Cortegana, Esteban Nogales-Fernández, Natalia Palazón-Carrión, Alejandro Martín García-Sancho, Eduardo Ríos-Herranz, Josep Gumà-Padrò, Mariano Provencio-Pulla, Antonio Rueda-Domínguez, Luis de la Cruz-Merino, Víctor Sánchez-Margalet","doi":"10.1186/s40170-025-00381-7","DOIUrl":"10.1186/s40170-025-00381-7","url":null,"abstract":"<p><strong>Background: </strong>Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma worldwide and is characterized by its heterogeneity. Although first-line therapy improves survival outcomes for DLBCL patients, approximately one third will relapse, often with a poor prognosis. Among the factors influencing prognosis and response to treatment in cancer patients, including those with lymphoma, overweight and obesity have emerged as significant considerations. However, the role of excess weight in DLBCL remains controversial, with studies reporting both negative and positive effects on cancer outcomes. In this translational substudy of the R2-GDP-GOTEL trial, we have evaluated the impact of excess weight as a predictor of treatment response and survival in patients with relapsed/refractory (R/R) DLBCL, and examining its relationship with immune cell dynamics.</p><p><strong>Methods: </strong>Of the 79 patients who received the R2-GDP scheme in the phase II trial, weight and height parameters were obtained in 75 patients before starting treatment. Blood samples were analyzed by flow cytometry. Statistical analyses were performed to determine the prognostic value of overweight and obesity at baseline in R/R DLBCL patients.</p><p><strong>Results: </strong>Our results indicate that overweight (including obese) patients exhibit longer survival compared to patients of ideal weight. This group also demonstrated a reduction of regulatory T cells with supposedly protumor activity and an increase of Natural Killer (NK)-like T cells with supposedly antitumor activity. Additionally, we have found that excess weight correlates with better treatment response, associated with elevated levels of vitamin D and CD8 + NK cells.</p><p><strong>Conclusions: </strong>Our findings suggest that excess weight does not exacerbate the progression of DLBCL. Instead, it appears to confer a survival advantage and improve treatment response, with the immune system playing a possible pivotal role in mediating these effects.</p><p><strong>Trial registration: </strong>EudraCT, ID:2014-001620-29.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"12"},"PeriodicalIF":6.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881355/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glutathione peroxidase 4 (GPX4) and obesity interact to impact tumor progression and treatment response in triple negative breast cancer.","authors":"Emily N Devericks, Bennett H Brosnan, Alyssa N Ho, Elaine M Glenny, Hannah M Malian, Dorothy Teegarden, Michael K Wendt, Michael F Coleman, Stephen D Hursting","doi":"10.1186/s40170-025-00380-8","DOIUrl":"10.1186/s40170-025-00380-8","url":null,"abstract":"<p><strong>Introduction: </strong>Triple-negative breast cancer (TNBC), which tends to be more advanced when diagnosed and more aggressive than other breast cancer subtypes, is accelerated by obesity. Hypertrophic adipocytes and cancer cells exhibit increased oxidative stress and altered redox homeostasis, influencing therapeutic outcomes. Enzymes implicated in both redox regulation and TNBC include glutathione peroxidase 4 (GPX4; reduces lipid peroxides) and pyruvate carboxylase (PC; essential in oxidative stress protection). Using preclinical models, we characterized interactions between GPX4, PC, and oxidative stress in TNBC cells, and established effects of GPX4 suppression on TNBC progression. In TNBC cells, PC knockdown increased GPX4 expression, while GPX4 knockdown increased PC expression. GPX4 inhibition by erastin or RSL3 enhanced TNBC cell death in vitro, and antioxidants mitigated the cytotoxicity. In obese mice, GPX4 knockdown, versus scramble control: (i) reduced tumor burden following orthotopic transplantation of TNBC cells; and (ii) reduced lung metastasis following tail vein injection of TNBC cells in combination with chemotherapy (carboplatin) but not immunotherapy (anti-CTLA4 plus anti-PD1). We conclude that GPX4 and PC expression are inversely related in TNBC cells, and GPX4 and obesity interact to impact TNBC progression and treatment responses. Moreover, GPX4-mediated redox defense, alone or in combination with chemotherapy, is a targetable vulnerability for treating TNBC, including obesity-related TNBC.</p><p><strong>Implication: </strong>GPX4 suppression, alone or with current TNBC therapies, impacts outcomes in preclinical TNBC models with or without obesity and offers a new, plausible mechanistic target for TNBC treatment.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"11"},"PeriodicalIF":6.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11863593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143499303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serine starvation suppresses the progression of esophageal cancer by regulating the synthesis of purine nucleotides and NADPH.","authors":"Hui Jie, Jing Wei, Zhuoling Li, Min Yi, Xinying Qian, Yan Li, Chunqi Liu, Chuan Li, Liang Wang, Pengchi Deng, Lunxu Liu, Xiaobo Cen, Yinglan Zhao","doi":"10.1186/s40170-025-00376-4","DOIUrl":"10.1186/s40170-025-00376-4","url":null,"abstract":"<p><p>Serine metabolism provides important metabolic intermediates that support the rapid proliferation of tumor cells. However, the role of serine metabolism in esophageal squamous cell carcinoma (ESCC) and the underlying mechanism remains unclear. Here, we show that serine starvation predominantly inhibits ESCC cell proliferation by suppressing purine nucleotides and NADPH synthesis. Mechanistically, serine depletion led to the accumulation of aminoimidazole carboxamide ribonucleoside (AICAR), an intermediate metabolite of de novo purine synthesis, and AMP/ATP ratio. These increases activated 5'-AMP-activated kinase (AMPK), which subsequently inhibited the mTORC1 pathway by phosphorylating Raptor at Ser792. Moreover, serine depletion decreased NADPH level followed by elevated reactive oxygen species (ROS) production and DNA damage, which induced p53-p21 mediated G1 phase cell cycle arrest. Conversely, serine starvation activated transcription factor 4 (ATF4)-mediated robust expression of phosphoserine aminotransferase 1 (PSAT1) which in turn promoted compensatory endogenous serine synthesis, thus maintaining ESCC cell survival under serine-limited conditions. Accordingly, serine deprivation combined with PSAT1 inhibition significantly suppressed ESCC tumor growth both in vitro and in vivo. Taken together, our findings demonstrate that serine starvation suppresses the proliferation of ESCC cells by disturbing the synthesis of purine nucleotides and NADPH, and the combination of serine deprivation and PSAT1 inhibition significantly impairs ESCC tumor growth. Our study provides a theoretical basis for targeting serine metabolism as a potential therapeutic strategy for ESCC.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"10"},"PeriodicalIF":6.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactate metabolism in clonal plasma cells and its therapeutic implications in multiple myeloma patients with elevated serum LDH levels.","authors":"Yogesh Chawla, Emilie I Anderson, Matthew Smith, Sonia Jain, Laura A Evans, Jadee Neff, Jin Sung Jang, Isas K Vazquez Rosario, Dragan Jevremovic, Xuan-Mai Petterson, Sinto Sebastian, Rafael Fonseca, Shaji K Kumar, Taro Hitosugi, Wilson I Gonsalves","doi":"10.1186/s40170-025-00379-1","DOIUrl":"10.1186/s40170-025-00379-1","url":null,"abstract":"<p><strong>Introduction: </strong>This study aimed to evaluate the metabolic differences between MM cells derived from patients with elevated serum LDH levels and those without elevated serum LDH levels to identify biological differences that could be exploited for therapeutic purposes.</p><p><strong>Methods: </strong>We performed transcriptome assessments of CD138 + MM cells derived from patients with elevated serum LDH levels compared to those without elevated serum LDH levels and validated the findings in a larger public dataset. Functional metabolic assessments of our findings were performed using a combination of stable isotope resolved metabolomics (SIRM), bioenergetic flux measurement assays, and live cell analysis in human myeloma cell lines and primary MM patient cells.</p><p><strong>Results: </strong>We identified SLC16A1, responsible for the formation of MCT1, a well-defined bi-directional transporter of lactate in and out of a cell with a predilection to importing extracellular lactate, as differentially expressed between the two groups. This finding was functionally confirmed by higher membranous MCT1 protein expression and SIRM on MM cells derived from patients with elevated serum LDH levels compared to those without elevated serum LDH levels. Finally, disrupting lactate transport in and out of CD138 + MM cells was maximally achievable only with dual inhibition of MCT1 and its partner, MCT4, which was preferentially more cytotoxic in MM cells derived from patients with elevated serum levels of LDH.</p><p><strong>Conclusion: </strong>MCT1 mRNA and protein expression distinguish MM cells derived from patients with elevated serum LDH levels from those without elevated serum LDH levels. However, only dual inhibition of MCT1 and MCT4 can disrupt lactate transport in multiple myeloma (MM) cells, with preferential cytotoxicity in MM cells from patients with high serum LDH levels.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"9"},"PeriodicalIF":6.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carboxylesterase 1-mediated endocannabinoid metabolism in skin: role in melanoma progression in BRaf^V600E/Pten^-/- mice.","authors":"Veronika Morozova, Daniele Pellegata, Roch-Philippe Charles, Jürg Gertsch","doi":"10.1186/s40170-025-00378-2","DOIUrl":"10.1186/s40170-025-00378-2","url":null,"abstract":"<p><strong>Background: </strong>Melanoma is a highly aggressive skin cancer with a poor prognosis. The endocannabinoids 2-arachidonoylgylcerol (2-AG) and anandamide have been linked to melanoma progression, though their roles remain unclear. We hypothesized that the 2-AG-arachidonate-prostaglandin axis could drive aggressive melanoma progression.</p><p><strong>Methods: </strong>The genetically engineered melanoma mouse model B6-Tyr::CreER^T2; BRaf^CA; Pten^loxP was characterized by targeted metabolomics. Functionally expressed serine hydrolases in the tumor tissue were identified by chemoproteomics. Pharmacological inhibition of carboxylesterase 1 (CES1) was achieved through chronic in vivo i.p. treatment with JZL184 (10 mg/kg daily), confirmed by activity-based protein profiling (ABPP) and targeted lipidomics. CES1-mediated 2-AG hydrolysis was further confirmed in radiotracer-based assays using CES1-transfected cell lines.</p><p><strong>Results: </strong>The diacylglycerol and protein kinase C activator 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG) was significantly elevated in the nodular-like melanoma tissues, along with 2-AG and arachidonic acid (ARA), compared to normal skin. AEA and other N-acylethanolamines were decreased, while, notably, prostaglandin levels remained unchanged. Significant changes in the levels of neuromodulators and neurotransmitters, including serotonin and adenosine, were observed. Pronounced differences between serine hydrolase activity in normal skin and melanoma tissue were identified by ABPP. Intriguingly, CES1 was identified as the only 2-AG-hydrolyzing enzyme in this melanoma tissue, as MAGL and ABHD6/12 were not expressed. The MAGL inhibitor JZL184 also efficiently inhibited CES1 in vitro and in vivo, increasing glycerol esters and reducing tumor progression. Additionally, scRNA-seq data from previous studies revealed divergent MAGL/CES1 expression patterns across different human melanoma subtypes.</p><p><strong>Conclusions: </strong>A role of CES1 expression in skin is demonstrated for the first time. Our study suggests that 2-AG degradation to arachidonate favors melanoma progression, either reflecting the carcinogenic role of ARA or that monoacylglycerols like 2-AG and/or other CES1 substrates may exert antitumor effects, indicating that CES1 could be a potential therapeutic target. CES1 expression and high SAG, 2-AG, and ARA levels may be a signature of specific BRAF-driven malignant melanoma subtypes which are associated with discrete metabolic adaptations.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"8"},"PeriodicalIF":6.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11817774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}