Cancer & Metabolism最新文献

筛选
英文 中文
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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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
Pancreatic cancer tumor organoids exhibit subtype-specific differences in metabolic profiles. 胰腺癌肿瘤器官组织的代谢特征表现出亚型特异性差异。
IF 6 3区 医学
Cancer & Metabolism Pub Date : 2024-10-03 DOI: 10.1186/s40170-024-00357-z
Hassan A Ali, Joanna M Karasinska, James T Topham, Danisha Johal, Steve Kalloger, Andrew Metcalfe, Cassia S Warren, Anthony Miyagi, Lan V Tao, Maya Kevorkova, Shawn C Chafe, Paul C McDonald, Shoukat Dedhar, Seth J Parker, Daniel J Renouf, David F Schaeffer
{"title":"Pancreatic cancer tumor organoids exhibit subtype-specific differences in metabolic profiles.","authors":"Hassan A Ali, Joanna M Karasinska, James T Topham, Danisha Johal, Steve Kalloger, Andrew Metcalfe, Cassia S Warren, Anthony Miyagi, Lan V Tao, Maya Kevorkova, Shawn C Chafe, Paul C McDonald, Shoukat Dedhar, Seth J Parker, Daniel J Renouf, David F Schaeffer","doi":"10.1186/s40170-024-00357-z","DOIUrl":"10.1186/s40170-024-00357-z","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease characterized by complex metabolic rewiring that enables growth in changing nutrient availability and oxygen conditions. Transcriptome-based prognostic PDAC tumor subtypes, known as 'basal-like' and 'classical' subtypes are associated with differences in metabolic gene expression including genes involved in glycolysis. Tumor subtype-specific metabolism phenotypes may provide new targets for treatment development in PDAC, but their functional relevance has not been fully elucidated. We aimed to investigate differences in metabolic profiles and transcriptomes in tumor models derived from patients with basal-like and classical tumors.</p><p><strong>Methods: </strong>Patient-derived organoids (PDOs) were established from tumor biopsies collected from patients with metastatic PDAC, including three PDOs from basal-like and five PDOs from classical tumors. Metabolic analyses included assessment of differences in metabolic activity using Seahorse Glycolysis and Mito Stress tests and <sup>13</sup>C-glucose metabolites tracing analysis. In order to investigate the influence of mitochondrial pyruvate transport on metabolic differences, PDOs were treated with the mitochondrial pyruvate carrier 1 (MPC1) inhibitor UK-5099. Prognostic relevance of MPC1 was determined using a tumor tissue microarray (TMA) in resectable, and proteomics profiling in metastatic PDAC datasets. Whole genome and transcriptome sequencing, differential gene expression and gene set enrichment analyses were performed in PDOs.</p><p><strong>Results: </strong>Metastatic PDAC PDOs showed subtype-specific differences in glycolysis and oxidative phosphorylation (OXPHOS). Basal-like tumor-derived PDOs had a lower baseline extracellular acidification rate, but higher glycolytic reserves and oxygen consumption rate (OCR) than classical tumor-derived PDOs. OCR difference was eliminated following treatment with UK-5099. In the <sup>13</sup>C-glucose metabolites tracing experiment, a basal-like tumor PDO showed lower fractions of some M + 2 metabolites but higher sensitivity to UK-5099 mediated reduction in M + 2 metabolites than a classical tumor PDO. Protein level analyses revealed lower MPC1 protein levels in basal-like PDAC cases and association of low MPC1 levels with clinicopathologic parameters of tumor aggressiveness in PDAC. PDO differential gene expression analyses identified additional subtype-specific cellular pathways and potential disease outcome biomarkers.</p><p><strong>Conclusions: </strong>Our findings point to distinct metabolic profiles in PDAC subtypes with basal-like tumor PDOs showing higher OXPHOS and sensitivity to MPC1 inhibition. Subtypes-specific metabolic vulnerabilities may be exploited for selective therapeutic targeting.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11448267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370977","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
Metabolism of primary high-grade serous ovarian carcinoma (HGSOC) cells under limited glutamine or glucose availability 原发性高级别浆液性卵巢癌(HGSOC)细胞在谷氨酰胺或葡萄糖供应受限情况下的新陈代谢
IF 5.9 3区 医学
Cancer & Metabolism Pub Date : 2024-09-16 DOI: 10.1186/s40170-024-00355-1
Daniela Šimčíková, Dominik Gardáš, Tomáš Pelikán, Lukáš Moráň, Martin Hruda, Kateřina Hložková, Tiziana Pivetta, Michal Hendrych, Júlia Starková, Lukáš Rob, Petr Vaňhara, Petr Heneberg
{"title":"Metabolism of primary high-grade serous ovarian carcinoma (HGSOC) cells under limited glutamine or glucose availability","authors":"Daniela Šimčíková, Dominik Gardáš, Tomáš Pelikán, Lukáš Moráň, Martin Hruda, Kateřina Hložková, Tiziana Pivetta, Michal Hendrych, Júlia Starková, Lukáš Rob, Petr Vaňhara, Petr Heneberg","doi":"10.1186/s40170-024-00355-1","DOIUrl":"https://doi.org/10.1186/s40170-024-00355-1","url":null,"abstract":"High-grade serous ovarian carcinoma (HGSOC) is the most common and aggressive subtype of epithelial ovarian carcinoma. It is primarily diagnosed at stage III or IV when the 5-year survival rate ranges between 20% and 40%. Here, we aimed to validate the hypothesis, based on HGSOC cell lines, that proposed the existence of two distinct groups of HGSOC cells with high and low oxidative phosphorylation (OXPHOS) metabolism, respectively, which are associated with their responses to glucose and glutamine withdrawal. We isolated and cultivated primary cancer cell cultures from HGSOC and nontransformed ovarian fibroblasts from the surrounding ovarium of 45 HGSOC patients. We tested the metabolic flexibility of the primary cells, particularly in response to glucose and glutamine depletion, analyzed and modulated endoplasmic reticulum stress, and searched for indices of the existence of previously reported groups of HGSOC cells with high and low OXPHOS metabolism. The primary HGSOC cells did not form two groups with high and low OXPHOS that responded differently to glucose and glutamine availabilities in the cell culture medium. Instead, they exhibited a continuum of OXPHOS phenotypes. In most tumor cell isolates, the responses to glucose or glutamine withdrawal were mild and surprisingly correlated with those of nontransformed ovarian fibroblasts from the same patients. The growth of tumor-derived cells in the absence of glucose was positively correlated with the lipid trafficking regulator FABP4 and was negatively correlated with the expression levels of HK2 and HK1. The correlations between the expression of electron transport chain (ETC) proteins and the oxygen consumption rates or extracellular acidification rates were weak. ER stress markers were strongly expressed in all the analyzed tumors. ER stress was further potentiated by tunicamycin but not by the recently proposed ER stress inducers based on copper(II)-phenanthroline complexes. ER stress modulation increased autophagy in tumor cell isolates but not in nontransformed ovarian fibroblasts. Analysis of the metabolism of primary HGSOC cells rejects the previously proposed hypothesis that there are distinct groups of HGSOC cells with high and low OXPHOS metabolism that respond differently to glutamine or glucose withdrawal and are characterized by ETC protein levels.","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253333","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
PAF1/HIF1α axis rewires the glycolytic metabolism to fuel aggressiveness of pancreatic cancer. PAF1/HIF1α轴重构了糖代谢,助长了胰腺癌的侵袭性。
IF 6 3区 医学
Cancer & Metabolism Pub Date : 2024-09-06 DOI: 10.1186/s40170-024-00354-2
Ayoola O Ogunleye, Neelanjana Gayen, Sanchita Rauth, Saravanakumar Marimuthu, Rama Krishna Nimmakayala, Zahraa W Alsafwani, Jesse L Cox, Surinder K Batra, Moorthy P Ponnusamy
{"title":"PAF1/HIF1α axis rewires the glycolytic metabolism to fuel aggressiveness of pancreatic cancer.","authors":"Ayoola O Ogunleye, Neelanjana Gayen, Sanchita Rauth, Saravanakumar Marimuthu, Rama Krishna Nimmakayala, Zahraa W Alsafwani, Jesse L Cox, Surinder K Batra, Moorthy P Ponnusamy","doi":"10.1186/s40170-024-00354-2","DOIUrl":"10.1186/s40170-024-00354-2","url":null,"abstract":"<p><strong>Background: </strong>PAF1/PD2 deregulation contributes to tumorigenesis, drug resistance, and cancer stem cell maintenance in Pancreatic Cancer (PC). Recent studies demonstrate that metabolic reprogramming plays a role in PC progression, but the mechanism is poorly understood. Here, we focused on examining the role of PAF1/PD2 in the metabolic rewiring of PC.</p><p><strong>Methods: </strong>Cell lines were transfected with shRNAs to knockdown PAF1/PD2. Metabolic genes regulated by PAF1/PD2 were identified by qPCR/western blot, and metabolic assays were performed. Immunoprecipitations/ChIP were performed to identify PAF1/PD2 protein partners and confirm PAF1/HIF1α sub-complex binding to LDHA.</p><p><strong>Results: </strong>PAF1 and LDHA showed progressively increased expression in human pancreatic tumor sections. Aerobic glycolysis genes were downregulated in PAF1-depleted PC cells. Metabolic assays indicated a decreased lactate production and glucose uptake in knockdown cells. Furthermore, PAF1/PD2 depletion showed a reduced glycolytic rate and increased oxidative phosphorylation by ECAR and OCR analysis. Interestingly, we identified that HIF1α interacts and co-localizes with PAF1, specifically in PC cells. We also observed that the PAF1/PD2-HIF1α complex binds to the LDHA promoter to regulate its expression, reprogramming the metabolism to utilize the aerobic glycolysis pathway preferentially.</p><p><strong>Conclusion: </strong>Overall, the results indicate that PAF1/PD2 rewires PC metabolism by interacting with HIF1α to regulate the expression of LDHA.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145258","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
Real-time assessment of relative mitochondrial ATP synthesis response against inhibiting and stimulating substrates (MitoRAISE). 实时评估线粒体 ATP 合成对抑制底物和刺激底物的相对反应(MitoRAISE)。
IF 6 3区 医学
Cancer & Metabolism Pub Date : 2024-08-29 DOI: 10.1186/s40170-024-00353-3
Eun Sol Chang, Kyoung Song, Ji-Young Song, Minjung Sung, Mi-Sook Lee, Jung Han Oh, Ji-Yeon Kim, Yeon Hee Park, Kyungsoo Jung, Yoon-La Choi
{"title":"Real-time assessment of relative mitochondrial ATP synthesis response against inhibiting and stimulating substrates (MitoRAISE).","authors":"Eun Sol Chang, Kyoung Song, Ji-Young Song, Minjung Sung, Mi-Sook Lee, Jung Han Oh, Ji-Yeon Kim, Yeon Hee Park, Kyungsoo Jung, Yoon-La Choi","doi":"10.1186/s40170-024-00353-3","DOIUrl":"10.1186/s40170-024-00353-3","url":null,"abstract":"<p><strong>Background: </strong>Mitochondria are known to synthesize adenosine triphosphate (ATP) through oxidative phosphorylation. Understanding and accurately measuring mitochondrial ATP synthesis rate can provide insights into the functional status of mitochondria and how it contributes to overall cellular energy homeostasis. Traditional methods only estimate mitochondrial function by measuring ATP levels at a single point in time or through oxygen consumption rates. This study introduced the relative mitochondrial ATP synthesis response against inhibiting and stimulating substrates (MitoRAISE), designed to detect real-time changes in ATP levels as the cells respond to substrates.</p><p><strong>Methods: </strong>The sensitivity and specificity of the MitoRAISE assay were verified under various conditions, including the isolation of mitochondria, variations in cell numbers, cells exhibiting mitochondrial damage, and heterogeneous mixtures. Using peripheral blood mononuclear cells (PBMCs), we analyzed MitoRAISE data from 19 patients with breast cancer and 23 healthy women.</p><p><strong>Results: </strong>The parameters observed in the MitoRAISE data increased depending on the quantity of isolated mitochondria and cell count, whereas it remained unmeasured in mitochondrial-damaged cell lines. Basal ATP, rotenone response, malonate response, and mitochondrial DNA copy numbers were lower in PBMCs from patients with breast cancer than in those from healthy women.</p><p><strong>Conclusions: </strong>The MitoRAISE assay has demonstrated its sensitivity and specificity by measuring relative ATP synthesis rates under various conditions. We propose MitoRAISE assay as a potential tool for monitoring changes in the mitochondrial metabolic status associated with various diseases.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11363686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104582","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
The polyunsaturated fatty acid docosahexaenoic affects mitochondrial function in prostate cancer cells. 多不饱和脂肪酸二十二碳六烯酸会影响前列腺癌细胞的线粒体功能。
IF 6 3区 医学
Cancer & Metabolism Pub Date : 2024-08-07 DOI: 10.1186/s40170-024-00348-0
Guilherme Henrique Tamarindo, Caroline Fidalgo Ribeiro, Alana Della Torre Silva, Alex Castro, Ícaro Putinhon Caruso, Fátima Pereira Souza, Sebastião Roberto Taboga, Massimo Loda, Rejane Maira Góes
{"title":"The polyunsaturated fatty acid docosahexaenoic affects mitochondrial function in prostate cancer cells.","authors":"Guilherme Henrique Tamarindo, Caroline Fidalgo Ribeiro, Alana Della Torre Silva, Alex Castro, Ícaro Putinhon Caruso, Fátima Pereira Souza, Sebastião Roberto Taboga, Massimo Loda, Rejane Maira Góes","doi":"10.1186/s40170-024-00348-0","DOIUrl":"10.1186/s40170-024-00348-0","url":null,"abstract":"<p><strong>Background: </strong>Prostate cancer (PCa) shows a rewired metabolism featuring increased fatty acid uptake and synthesis via de novo lipogenesis, both sharply related to mitochondrial physiology. The docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid (PUFA) that exerts its antitumoral properties via different mechanisms, but its specific action on mitochondria in PCa is not clear. Therefore, we investigated whether the DHA modulates mitochondrial function in PCa cell lines.</p><p><strong>Methods: </strong>Here, we evaluated mitochondrial function of non-malignant PNT1A and the castration-resistant (CRPC) prostate 22Rv1 and PC3 cell lines in response to DHA incubation. For this purpose, we used Seahorse extracellular flux assay to assess mitochondria function, [<sup>14</sup>C]-glucose to evaluate its oxidation as well as its contribution to fatty acid synthesis, <sup>1</sup>H-NMR for metabolite profile determination, MitoSOX for superoxide anion production, JC-1 for mitochondrial membrane polarization, mass spectrometry for determination of phosphatidylglycerol levels and composition, staining with MitoTracker dye to assess mitochondrial morphology under super-resolution in addition to Transmission Electron Microscopy, In-Cell ELISA for COX-I and SDH-A protein expression and flow cytometry (Annexin V and 7-AAD) for cell death estimation.</p><p><strong>Results: </strong>In all cell lines DHA decreased basal respiratory activity, ATP production, and the spare capacity in mitochondria. Also, the omega-3 induced mitochondrial hyperpolarization, ROS overproduction and changes in membrane phosphatidylglycerol composition. In PNT1A, DHA led to mitochondrial fragmentation and it increased glycolysis while in cancer cells it stimulated glucose oxidation, but decreased de novo lipogenesis specifically in 22Rv1, indicating a metabolic shift. In all cell lines, DHA modulated several metabolites related to energy metabolism and it was incorporated in phosphatidylglycerol, a precursor of cardiolipin, increasing the unsaturation index in the mitochondrial membrane. Accordingly, DHA triggered cell death mainly in PNT1A and 22Rv1.</p><p><strong>Conclusion: </strong>In conclusion, mitochondrial metabolism is significantly affected by the PUFA supplementation to the point that cells are not able to proliferate or survive under DHA-enriched condition. Moreover, combination of DHA supplementation with inhibition of metabolism-related pathways, such as de novo lipogenesis, may be synergistic in castration-resistant prostate cancer.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11308158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901033","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
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
相关产品
×
本文献相关产品
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信