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A whole food, plant-based diet reduces amino acid levels in patients with metastatic breast cancer.
IF 6 3区 医学
Cancer & Metabolism Pub Date : 2024-12-19 DOI: 10.1186/s40170-024-00368-w
TashJaé Q Scales, Bradley Smith, Lisa M Blanchard, Nellie Wixom, Emily T Tuttle, Brian J Altman, Luke J Peppone, Joshua Munger, Thomas M Campbell, Erin K Campbell, Isaac S Harris
{"title":"A whole food, plant-based diet reduces amino acid levels in patients with metastatic breast cancer.","authors":"TashJaé Q Scales, Bradley Smith, Lisa M Blanchard, Nellie Wixom, Emily T Tuttle, Brian J Altman, Luke J Peppone, Joshua Munger, Thomas M Campbell, Erin K Campbell, Isaac S Harris","doi":"10.1186/s40170-024-00368-w","DOIUrl":"https://doi.org/10.1186/s40170-024-00368-w","url":null,"abstract":"<p><strong>Background: </strong>Amino acids are critical to tumor survival. Tumors can acquire amino acids from the surrounding microenvironment, including the serum. Limiting dietary amino acids is suggested to influence their serum levels. Further, a plant-based diet is reported to contain fewer amino acids than an animal-based diet. The extent to which a plant-based diet lowers the serum levels of amino acids in patients with cancer is unclear.</p><p><strong>Methods: </strong>Patients with metastatic breast cancer (n = 17) were enrolled in a clinical trial with an ad libitum whole food, plant-based diet for 8 weeks without calorie or portion restriction. Dietary changes by participants were monitored using a three-day food record. Serum was collected from participants at baseline and 8 weeks. Food records and serum were analyzed for metabolic changes.</p><p><strong>Results: </strong>We found that a whole food, plant-based diet resulted in a lower intake of calories, fat, and amino acids and higher levels of fiber. Additionally, body weight, serum insulin, and IGF were reduced in participants. The diet contained lower levels of essential and non-essential amino acids, except for arginine (glutamine and asparagine were not measured). Importantly, the lowered dietary intake of amino acids translated to reduced serum levels of amino acids in participants (5/9 essential amino acids; 4/11 non-essential amino acids).</p><p><strong>Conclusions: </strong>These findings provide a tractable approach to limiting amino acid levels in persons with cancer. This data lays a foundation for studying the relationship between amino acids in patients and tumor progression. Further, a whole-food, plant-based diet has the potential to synergize with cancer therapies that exploit metabolic vulnerabilities.</p><p><strong>Trial registration: </strong>The clinical trial was registered with ClinicalTrials.gov identifier NCT03045289 on 2017-02-07.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"12 1","pages":"38"},"PeriodicalIF":6.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863410","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}
引用次数: 0
PFKFB3-dependent redox homeostasis and DNA repair support cell survival under EGFR-TKIs in non-small cell lung carcinoma.
IF 6 3区 医学
Cancer & Metabolism Pub Date : 2024-12-18 DOI: 10.1186/s40170-024-00366-y
Nadiia Lypova, Susan M Dougherty, Brian F Clem, Jing Feng, Xinmin Yin, Xiang Zhang, Xiaohong Li, Jason A Chesney, Yoannis Imbert-Fernandez
{"title":"PFKFB3-dependent redox homeostasis and DNA repair support cell survival under EGFR-TKIs in non-small cell lung carcinoma.","authors":"Nadiia Lypova, Susan M Dougherty, Brian F Clem, Jing Feng, Xinmin Yin, Xiang Zhang, Xiaohong Li, Jason A Chesney, Yoannis Imbert-Fernandez","doi":"10.1186/s40170-024-00366-y","DOIUrl":"https://doi.org/10.1186/s40170-024-00366-y","url":null,"abstract":"<p><strong>Background: </strong>The efficacy of tyrosine kinase inhibitors (TKIs) targeting the EGFR is limited due to the persistence of drug-tolerant cell populations, leading to therapy resistance. Non-genetic mechanisms, such as metabolic rewiring, play a significant role in driving lung cancer cells into the drug-tolerant state, allowing them to persist under continuous drug treatment.</p><p><strong>Methods: </strong>Our study employed a comprehensive approach to examine the impact of the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) on the adaptivity of lung cancer cells to EGFR TKI therapies. We conducted metabolomics to trace glucose rerouting in response to PFKFB3 inhibition during TKI treatment. Live cell imaging and DCFDA oxidation were used to quantify levels of oxidation stress. Immunocytochemistry and Neutral Comet assay were employed to evaluate DNA integrity in response to therapy-driven oxidative stress.</p><p><strong>Results: </strong>Our metabolic profiling revealed that PFKFB3 inhibition significantly alters the metabolic profile of TKI-treated cells. It limited glucose utilization in the polyol pathway, glycolysis, and TCA cycle, leading to a depletion of ATP levels. Furthermore, pharmacological inhibition of PFKFB3 overcome TKI-driven redox capacity by diminishing the expression of glutathione peroxidase 4 (GPX4), thereby exacerbating oxidative stress. Our study also unveiled a novel role of PFKFB3 in DNA oxidation and damage by controlling the expression of DNA-glycosylases involved in base excision repair. Consequently, PFKFB3 inhibition improved the cytotoxicity of EGFR-TKIs by facilitating ROS-dependent cell death.</p><p><strong>Conclusions: </strong>Our results suggest that PFKFB3 inhibition reduces glucose utilization and DNA damage repair, limiting the adaptivity of the cells to therapy-driven oxidative stress and DNA integrity insults. Inhibiting PFKFB3 can be an effective strategy to eradicate cancer cells surviving under EGFR TKI therapy before they enter the drug-resistant state. These findings may have potential implications in the development of new therapies for drug-resistant cancer treatment.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"12 1","pages":"37"},"PeriodicalIF":6.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852908","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}
引用次数: 0
TDO2 inhibition counters Benzo[a]pyrene-induced immune evasion and suppresses tumorigenesis in lung adenocarcinoma. 抑制 TDO2 可抵消苯并[a]芘诱导的免疫逃避并抑制肺腺癌的肿瘤发生。
IF 6 3区 医学
Cancer & Metabolism Pub Date : 2024-11-26 DOI: 10.1186/s40170-024-00365-z
İsa Taş, Mücahit Varlı, Sultan Pulat, Hyun Bo Sim, Jong-Jin Kim, Hangun Kim
{"title":"TDO2 inhibition counters Benzo[a]pyrene-induced immune evasion and suppresses tumorigenesis in lung adenocarcinoma.","authors":"İsa Taş, Mücahit Varlı, Sultan Pulat, Hyun Bo Sim, Jong-Jin Kim, Hangun Kim","doi":"10.1186/s40170-024-00365-z","DOIUrl":"10.1186/s40170-024-00365-z","url":null,"abstract":"<p><strong>Introduction: </strong>Benzo[a]pyrene (BaP) is a toxic polycyclic aromatic hydrocarbon known as an exogenous AhR ligand. This study investigates the role of BaP in inducing immune checkpoint expression in lung adenocarcinoma (LUAD) and the underlying mechanisms involving the aryl hydrocarbon receptor (AhR) and tryptophan (Trp) metabolism.</p><p><strong>Methods: </strong>We assessed the expression of immune checkpoint molecules, including PD-L1 and ICOSL, in lung epithelial cell lines (BEAS-2B and H1975) exposed to BaP. The involvement of AhR in BaP-induced immune checkpoint expression was examined using AhR silencing (siAhR). Additionally, the role of Trp metabolism in BaP-mediated immune evasion was explored through culturing in Trp (-/+) condition media, treatments with the inhibitors of rate-limiting enzymes in Trp metabolism (TDO2 and IDO1) and analyses of Trp-catabolizing enzymes. The therapeutic potential of targeting Trp metabolism, specifically TDO2, was evaluated in vivo using C57BL/6 mice orthotopically inoculated with LUAD cells.</p><p><strong>Results: </strong>BaP exposure significantly upregulated the mRNA and surface expression of PD-L1 and ICOSL, with AhR playing a crucial role in this induction. Trp metabolism was found to enhance BaP-mediated immune evasion, as indicated by stronger induction of immune checkpoints in Trp (+) media and the upregulation of Trp-catabolizing enzymes. TDO2 inhibition markedly suppressed the surface expression of PD-L1 and ICOSL, demonstrating the importance of Trp metabolism in BaP-induced immune evasion. Further analysis confirmed the high TDO2 expression in lung adenocarcinoma and its association with poor patient survival. Using an orthotopic implantation mouse model, we demonstrated the inhibitory effect of two different TDO2 inhibitors on tumorigenesis, immune checkpoints, and tryptophan metabolism.</p><p><strong>Conclusions: </strong>This study highlights the key mechanisms behind BaP-induced immune evasion in LUAD, particularly through the TDO2/AhR axis. It reveals how TDO2 inhibitors can counteract immune checkpoint activation and boost anti-tumor immunity, suggesting new paths for targeted lung cancer immunotherapy. The findings significantly improve our understanding of immune evasion in LUAD and underscore the therapeutic promise of TDO2 inhibition.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"12 1","pages":"36"},"PeriodicalIF":6.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11590479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726231","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}
引用次数: 0
Glutaminolysis is associated with mitochondrial pathway activation and can be therapeutically targeted in glioblastoma. 谷氨酰胺溶解与线粒体通路激活有关,可以作为胶质母细胞瘤的治疗靶点。
IF 6 3区 医学
Cancer & Metabolism Pub Date : 2024-11-19 DOI: 10.1186/s40170-024-00364-0
Kenji Miki, Mikako Yagi, Ryusuke Hatae, Ryosuke Otsuji, Takahiro Miyazaki, Katsuhiro Goto, Daiki Setoyama, Yutaka Fujioka, Yuhei Sangatsuda, Daisuke Kuga, Nayuta Higa, Tomoko Takajo, Yonezawa Hajime, Toshiaki Akahane, Akihide Tanimoto, Ryosuke Hanaya, Yuya Kunisaki, Takeshi Uchiumi, Koji Yoshimoto
{"title":"Glutaminolysis is associated with mitochondrial pathway activation and can be therapeutically targeted in glioblastoma.","authors":"Kenji Miki, Mikako Yagi, Ryusuke Hatae, Ryosuke Otsuji, Takahiro Miyazaki, Katsuhiro Goto, Daiki Setoyama, Yutaka Fujioka, Yuhei Sangatsuda, Daisuke Kuga, Nayuta Higa, Tomoko Takajo, Yonezawa Hajime, Toshiaki Akahane, Akihide Tanimoto, Ryosuke Hanaya, Yuya Kunisaki, Takeshi Uchiumi, Koji Yoshimoto","doi":"10.1186/s40170-024-00364-0","DOIUrl":"10.1186/s40170-024-00364-0","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma is an aggressive cancer that originates from abnormal cell growth in the brain and requires metabolic reprogramming to support tumor growth. Metabolic reprogramming involves the upregulation of various metabolic pathways. Although the activation of specific metabolic pathways in glioblastoma cell lines has been documented, the comprehensive profile of metabolic reprogramming and the role of each pathway in glioblastoma tissues in patients remain elusive.</p><p><strong>Methods: </strong>We analyzed 38 glioblastoma tissues. As a test set, we examined 20 tissues from Kyushu University Hospital, focusing on proteins related to several metabolic pathways, including glycolysis, the one-carbon cycle, glutaminolysis, and the mitochondrial tricarboxylic acid cycle. Subsequently, we analyzed an additional 18 glioblastoma tissues from Kagoshima University Hospital as a validation set. We also validated our findings using six cell lines, including U87, LN229, U373, T98G, and two patient-derived cells.</p><p><strong>Results: </strong>The levels of mitochondria-related proteins (COX1, COX2, and DRP1) were correlated with each other and with glutaminolysis-related proteins (GLDH and GLS1). Conversely, their expression was inversely correlated with that of glycolytic proteins. Notably, inhibiting the glutaminolysis pathway in cell lines with high GLDH and GLS1 expression proved effective in suppressing tumor growth.</p><p><strong>Conclusions: </strong>Our findings confirm that glioblastoma tissues can be categorized into glycolytic-dominant and mitochondrial-dominant types, as previously reported. The mitochondrial-dominant type is also glutaminolysis-dominant. Therefore, inhibiting the glutaminolysis pathway may be an effective treatment for mitochondrial-dominant glioblastoma.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"12 1","pages":"35"},"PeriodicalIF":6.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675155","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}
引用次数: 0
Complete inhibition of liver acetyl-CoA carboxylase activity is required to exacerbate liver tumorigenesis in mice treated with diethylnitrosamine. 在使用二乙基亚硝胺的小鼠体内,肝脏乙酰-CoA羧化酶活性的完全抑制是加剧肝脏肿瘤发生的必要条件。
IF 6 3区 医学
Cancer & Metabolism Pub Date : 2024-11-13 DOI: 10.1186/s40170-024-00363-1
Riya Shrestha, Calum S Vancuylenburg, Martina Beretta, Mingyan Zhou, Divya P Shah, Ellen M Olzomer, Sian L Richards, Kyle L Hoehn, Frances L Byrne
{"title":"Complete inhibition of liver acetyl-CoA carboxylase activity is required to exacerbate liver tumorigenesis in mice treated with diethylnitrosamine.","authors":"Riya Shrestha, Calum S Vancuylenburg, Martina Beretta, Mingyan Zhou, Divya P Shah, Ellen M Olzomer, Sian L Richards, Kyle L Hoehn, Frances L Byrne","doi":"10.1186/s40170-024-00363-1","DOIUrl":"10.1186/s40170-024-00363-1","url":null,"abstract":"<p><strong>Background: </strong>The metabolic pathway of de novo lipogenesis (DNL) is upregulated in fatty liver disease and liver cancer. Inhibitors of DNL are in development for the treatment of these disorders; however, our previous study showed that blocking DNL unexpectedly exacerbated liver tumorigenesis when liver acetyl-CoA carboxylase (ACC) 1 and 2 enzymes were deleted in mice treated with diethylnitrosamine (DEN) and fed high fat diet. Herein, we used 3 new approaches including ACC1 vs. ACC2 isotype-selective inhibition, delaying ACC inhibition until after carcinogen treatment, and feeding mice normal chow diet to better understand the impact of ACC inhibition on liver tumorigenesis.</p><p><strong>Methods: </strong>Six genotypes of female C57BL/6J mice with floxed ACC1 and/or ACC2 alleles were injected with DEN at 2 weeks of age followed by liver-specific knockout of ACC genes at 9 weeks. Mice were fed a normal chow diet and evaluated at 52 weeks for liver tumours.</p><p><strong>Results: </strong>Compared to the wildtype control group, no genotype decreased tumour multiplicity or burden; however, mice completely lacking liver ACC1 and ACC2 had > 5-fold increases in liver tumour multiplicity and burden.</p><p><strong>Conclusion: </strong>ACC inhibition exacerbated DEN-induced liver tumorigenesis only when both ACC isotypes were completely inhibited. The pro-tumour phenotype of ACC inhibition was strongly reproducible irrespective of chow or high fat feeding, and irrespective of ACC inhibition prior to or after DEN treatment. Retaining partial ACC activity at either isotype prevented tumour exacerbation in mice at risk for developing liver tumours.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"12 1","pages":"34"},"PeriodicalIF":6.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615340","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}
引用次数: 0
CYP19A1 regulates chemoresistance in colorectal cancer through modulation of estrogen biosynthesis and mitochondrial function. CYP19A1通过调节雌激素的生物合成和线粒体功能调节结直肠癌的化疗耐药性
IF 6 3区 医学
Cancer & Metabolism Pub Date : 2024-10-28 DOI: 10.1186/s40170-024-00360-4
Yang Wang, Qiang Ji, Ning Cao, Guijie Ge, Xiaomin Li, Xiangdong Liu, Yanqi Mi
{"title":"CYP19A1 regulates chemoresistance in colorectal cancer through modulation of estrogen biosynthesis and mitochondrial function.","authors":"Yang Wang, Qiang Ji, Ning Cao, Guijie Ge, Xiaomin Li, Xiangdong Liu, Yanqi Mi","doi":"10.1186/s40170-024-00360-4","DOIUrl":"10.1186/s40170-024-00360-4","url":null,"abstract":"<p><p>Chemoresistance remains a major challenge in the effective treatment of colorectal cancer (CRC), contributing to poor patient outcomes. While the molecular mechanisms underlying chemoresistance are complex and multifaceted, emerging evidence suggests that altered mitochondrial function and hormone signaling play crucial roles. In this study, we investigated the role of CYP19A1, a key enzyme in estrogen biosynthesis, in regulating chemoresistance in CRC. Using a combination of in vitro functional assays, transcriptomic analysis, and clinical data mining, we demonstrate that CYP19A1 expression is significantly upregulated in CRC cells and patient-derived samples compared to normal controls. Mechanistically, we found that CYP19A1 regulates chemoresistance through modulation of mitochondrial function and complex I activity, which is mediated by CYP19A1-dependent estrogen biosynthesis. Notably, targeted inhibition of CYP19A1 and complex I using specific inhibitors effectively reversed the chemoresistance of CRC cells to chemotherapeutic drugs. Moreover, analysis of the TCGA CRC dataset revealed that high CYP19A1 expression correlates with poor overall survival in chemotherapy-treated patients. Taken together, our findings uncover a novel role for CYP19A1 in regulating chemoresistance in CRC through modulation of mitochondrial function and estrogen signaling, and highlight the potential of targeting the CYP19A1/estrogen/complex I axis as a therapeutic strategy to overcome chemoresistance and improve patient outcomes.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"12 1","pages":"33"},"PeriodicalIF":6.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521076","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}
引用次数: 0
GCN2-SLC7A11 axis coordinates autophagy, cell cycle and apoptosis and regulates cell growth in retinoblastoma upon arginine deprivation. GCN2-SLC7A11轴协调自噬、细胞周期和细胞凋亡,并在精氨酸缺乏时调节视网膜母细胞瘤的细胞生长。
IF 6 3区 医学
Cancer & Metabolism Pub Date : 2024-10-26 DOI: 10.1186/s40170-024-00361-3
Dan Wang, Wai Kit Chu, Jason Cheuk Sing Yam, Chi Pui Pang, Yun Chung Leung, Alisa Sau Wun Shum, Sun-On Chan
{"title":"GCN2-SLC7A11 axis coordinates autophagy, cell cycle and apoptosis and regulates cell growth in retinoblastoma upon arginine deprivation.","authors":"Dan Wang, Wai Kit Chu, Jason Cheuk Sing Yam, Chi Pui Pang, Yun Chung Leung, Alisa Sau Wun Shum, Sun-On Chan","doi":"10.1186/s40170-024-00361-3","DOIUrl":"10.1186/s40170-024-00361-3","url":null,"abstract":"<p><strong>Background: </strong>Arginine deprivation was previously shown to inhibit retinoblastoma cell proliferation and induce cell death in vitro. However, the mechanisms by which retinoblastoma cells respond to arginine deprivation remain to be elucidated.</p><p><strong>Methods: </strong>The human-derived retinoblastoma cell lines Y79 and WERI-Rb-1 were subjected to arginine depletion, and the effects on inhibiting cell growth and survival were evaluated. This study investigated potential mechanisms, including autophagy, cell cycle arrest and apoptosis. Moreover, the roles of the general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1) signaling pathways in these processes were examined.</p><p><strong>Results: </strong>We demonstrated that arginine deprivation effectively inhibited the growth of retinoblastoma cells in vitro. This treatment caused an increase in the autophagic response. Additionally, prolonged arginine deprivation induced G2 cell cycle arrest and was accompanied by an increase in early apoptotic cells. Importantly, arginine depletion also induced the activation of GCN2 and the inhibition of mTOR signaling. We also discovered that the activation of SLC7A11 was regulated by GCN2 upon arginine deprivation. Knockdown of SLC7A11 rendered retinoblastoma cells partially resistant to arginine deprivation. Furthermore, we found that knockdown of GCN2 led to a decrease in the autophagic response in WERI-Rb-1 cells and arrested more cells in S phase, which was accompanied by fewer apoptotic cells. Moreover, knockdown of GCN2 induced the constant expression of ATF4 and the phosphorylation of 70S6K and 4E-BP1 regardless of arginine deprivation.</p><p><strong>Conclusions: </strong>Collectively, our findings suggest that the GCN2‒SLC7A11 axis regulates cell growth and survival upon arginine deprivation through coordinating autophagy, cell cycle arrest, and apoptosis in retinoblastoma cells. This work paves the way for the development of a novel treatment for retinoblastoma.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"12 1","pages":"31"},"PeriodicalIF":6.0,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11515237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495644","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}
引用次数: 0
RHOF promotes Snail1 lactylation by enhancing PKM2-mediated glycolysis to induce pancreatic cancer cell endothelial-mesenchymal transition. RHOF 通过增强 PKM2 介导的糖酵解促进 Snail1 乳化,从而诱导胰腺癌细胞的内皮-间充质转化。
IF 6 3区 医学
Cancer & Metabolism Pub Date : 2024-10-26 DOI: 10.1186/s40170-024-00362-2
Rui Zhao, Yanmin Yi, Han Liu, Jianwei Xu, Shuhai Chen, Dong Wu, Lei Wang, Feng Li
{"title":"RHOF promotes Snail1 lactylation by enhancing PKM2-mediated glycolysis to induce pancreatic cancer cell endothelial-mesenchymal transition.","authors":"Rui Zhao, Yanmin Yi, Han Liu, Jianwei Xu, Shuhai Chen, Dong Wu, Lei Wang, Feng Li","doi":"10.1186/s40170-024-00362-2","DOIUrl":"10.1186/s40170-024-00362-2","url":null,"abstract":"<p><strong>Background: </strong>The influence of the small Rho GTPase Rif (RHOF) on tumor growth, glycolysis, endothelial-mesenchymal transition (EMT), and the potential mechanism of RHOF in pancreatic cancer (PC) were explored.</p><p><strong>Methods: </strong>RHOF expression in PC tissues and cells was assessed by qRT-PCR and western blotting. The viability, proliferation, apoptosis, migration, and invasion of PC cells were assessed using CCK-8, colony formation, EdU, flow cytometry, scratch, and Transwell assays. The expression of EMT- and glycolysis-related proteins was determined using western blotting. The potential mechanisms of action of RHOF in PC were identified using bioinformatic analysis. The effects of RHOF were assessed in vivo using a xenograft mouse model.</p><p><strong>Results: </strong>PC cell proliferation, migration, and invasion are accelerated by RHOF overexpression, which inhibited apoptosis. RHOF overexpression promoted EMT and glycolysis as evidenced by a decrease in E-cadherin expression and an increase in N-cadherin, Vimentin, HK2, PKM2, and LDHA expression. Bioinformatic analysis indicated that RHOF activated EMT, glycolysis, and Myc targets and that c-Myc could bind to the PKM2 promoter. RHOF overexpression promotes the lactylation and nuclear translocation of Snail1. Silencing Snail1 reversed the promoting effects of RHOF and lactate on cell migration, invasion, and EMT. Moreover, in vivo tumor growth and EMT were inhibited by RHOF silencing.</p><p><strong>Conclusion: </strong>RHOF plays an oncogenic role in PC. c-Myc is upregulated by RHOF and promotes PKM2 transcription. PKM2 further induces glycolysis, and the lactate produced by glycolysis causes the lactylation of Snail1, ultimately promoting EMT.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"12 1","pages":"32"},"PeriodicalIF":6.0,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11515152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495645","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}
引用次数: 0
RNF2 promotes chondrosarcoma progression by regulating ubiquitination and degradation of CBX7. RNF2 通过调控 CBX7 的泛素化和降解促进软骨肉瘤的发展。
IF 6 3区 医学
Cancer & Metabolism Pub Date : 2024-10-25 DOI: 10.1186/s40170-024-00359-x
Yue Wu, Zheng Huang, Ping Luo, Zhong Xiang, Meng Zhang, Zhiwu Chen, Yalu Zhou, Jiameng Li
{"title":"RNF2 promotes chondrosarcoma progression by regulating ubiquitination and degradation of CBX7.","authors":"Yue Wu, Zheng Huang, Ping Luo, Zhong Xiang, Meng Zhang, Zhiwu Chen, Yalu Zhou, Jiameng Li","doi":"10.1186/s40170-024-00359-x","DOIUrl":"10.1186/s40170-024-00359-x","url":null,"abstract":"<p><strong>Objective: </strong>Chondrosarcoma (CHS) is resistant to conventional chemotherapy and radiotherapy and currently lacks effective treatment options when in advanced stages. Accordingly, this research investigated the mechanism of RNF2/CBX7 in CHS to drive the development of molecularly targeted drugs for CHS.</p><p><strong>Methods: </strong>RNF2 and CBX7 levels were detected in CHS cells and tissues. RNF2 and CBX7 expression was modulated through cell transfection to examine their effects on cell proliferation, apoptosis, migration, and angiogenesis. The correlation between RNF2 and CBX7 levels was determined, and the ubiquitination level of CBX7 was tested. Protein synthesis was blocked in RNF2-knockdown/overexpressing cells with CHX to assess the effect of RNF2 on CBX7 stability. JJ012 cells transfected with LV-sh-RNF2 were subcutaneously injected into nu/nu nude mice to ascertain the action of RNF2 in the growth and metastasis of CHS.</p><p><strong>Results: </strong>RNF2 was highly expressed in CHS cells and tissues. RNF2 knockdown curbed CHS cell proliferation, migration, and angiogenesis while promoting apoptosis. RNF2 knockdown in JJ012 cells upregulated CBX7 protein levels and reduced CBX7 ubiquitination, whilst RNF2 had no effect on CBX7 mRNA expression. CBX7 knockdown partially nullified the repressing effects of RNF2 knockdown on CHS cell proliferation, migration, and angiogenesis, and CBX7 overexpression partially abolished the promotional effects of RNF2 overexpression. LV-sh-RNF2 prominently restricted tumor growth and weight and declined lung metastatic nodules and Ki-67-positive cells in mice.</p><p><strong>Conclusion: </strong>RNF2 fosters CHS progression by elevating CBX7 degradation via the ubiquitination pathway.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"12 1","pages":"30"},"PeriodicalIF":6.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495646","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}
引用次数: 0
Unraveling the glycosphingolipid metabolism by leveraging transcriptome-weighted network analysis on neuroblastic tumors. 利用神经母细胞瘤转录组加权网络分析揭示糖磷脂代谢过程
IF 6 3区 医学
Cancer & Metabolism Pub Date : 2024-10-24 DOI: 10.1186/s40170-024-00358-y
Arsenij Ustjanzew, Annekathrin Silvia Nedwed, Roger Sandhoff, Jörg Faber, Federico Marini, Claudia Paret
{"title":"Unraveling the glycosphingolipid metabolism by leveraging transcriptome-weighted network analysis on neuroblastic tumors.","authors":"Arsenij Ustjanzew, Annekathrin Silvia Nedwed, Roger Sandhoff, Jörg Faber, Federico Marini, Claudia Paret","doi":"10.1186/s40170-024-00358-y","DOIUrl":"10.1186/s40170-024-00358-y","url":null,"abstract":"<p><strong>Background: </strong>Glycosphingolipids (GSLs) are membrane lipids composed of a ceramide backbone linked to a glycan moiety. Ganglioside biosynthesis is a part of the GSL metabolism, which involves sequential reactions catalyzed by specific enzymes that in part have a poor substrate specificity. GSLs are deregulated in cancer, thus playing a role as potential biomarkers for personalized therapy or subtype classification. However, the analysis of GSL profiles is complex and requires dedicated technologies, that are currently not included in the commonly utilized high-throughput assays adopted in contexts such as molecular tumor boards.</p><p><strong>Methods: </strong>In this study, we developed a method to discriminate the enzyme activity among the four series of the ganglioside metabolism pathway by incorporating transcriptome data and topological information of the metabolic network. We introduced three adjustment options for reaction activity scores (RAS) and demonstrated their application in both exploratory and comparative analyses by applying the method on neuroblastic tumors (NTs), encompassing neuroblastoma (NB), ganglioneuroblastoma (GNB), and ganglioneuroma (GN). Furthermore, we interpreted the results in the context of earlier published GSL measurements in the same tumors.</p><p><strong>Results: </strong>By adjusting RAS values using a weighting scheme based on network topology and transition probabilities (TPs), the individual series of ganglioside metabolism can be differentiated, enabling a refined analysis of the GSL profile in NT entities. Notably, the adjustment method we propose reveals the differential engagement of the ganglioside series between NB and GNB. Moreover, MYCN gene expression, a well-known prognostic marker in NTs, appears to correlate with the expression of therapeutically relevant gangliosides, such as GD2. Using unsupervised learning, we identified subclusters within NB based on altered GSL metabolism.</p><p><strong>Conclusion: </strong>Our study demonstrates the utility of adjusting RAS values in discriminating ganglioside metabolism subtypes, highlighting the potential for identifying novel cancer subgroups based on sphingolipid profiles. These findings contribute to a better understanding of ganglioside dysregulation in NT and may have implications for stratification and targeted therapeutic strategies in these tumors and other tumor entities with a deregulated GSL metabolism.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"12 1","pages":"29"},"PeriodicalIF":6.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11515559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495647","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}
引用次数: 0
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