Cancer & Metabolism最新文献

{"title":"Metabolic plasticity of IDH1<i>-mutant</i> glioma cell lines is responsible for low sensitivity to glutaminase inhibition.","authors":"Victor Ruiz-Rodado,&nbsp;Adrian Lita,&nbsp;Tyrone Dowdy,&nbsp;Orieta Celiku,&nbsp;Alejandra Cavazos Saldana,&nbsp;Herui Wang,&nbsp;Chun Zhang Yang,&nbsp;Raj Chari,&nbsp;Aiguo Li,&nbsp;Wei Zhang,&nbsp;Hua Song,&nbsp;Meili Zhang,&nbsp;Susie Ahn,&nbsp;Dionne Davis,&nbsp;Xiang Chen,&nbsp;Zhengping Zhuang,&nbsp;Christel Herold-Mende,&nbsp;Kylie J Walters,&nbsp;Mark R Gilbert,&nbsp;Mioara Larion","doi":"10.1186/s40170-020-00229-2","DOIUrl":"https://doi.org/10.1186/s40170-020-00229-2","url":null,"abstract":"<p><strong>Background: </strong>Targeting glutamine metabolism in cancer has become an increasingly vibrant area of research. Mutant IDH1 (IDH1 ^<i>mut</i> ) gliomas are considered good candidates for targeting this pathway because of the contribution of glutamine to their newly acquired function: synthesis of 2-hydroxyglutarate (2HG).</p><p><strong>Methods: </strong>We have employed a combination of ¹³C tracers including glutamine and glucose for investigating the metabolism of patient-derived IDH1 ^<i>mut</i> glioma cell lines through NMR and LC/MS. Additionally, genetic loss-of-function (in vitro and in vivo) approaches were performed to unravel the adaptability of these cell lines to the inhibition of glutaminase activity.</p><p><strong>Results: </strong>We report the adaptability of IDH1 ^<i>mut</i> cells' metabolism to the inhibition of glutamine/glutamate pathway. The glutaminase inhibitor CB839 generated a decrease in the production of the downstream metabolites of glutamate, including those involved in the TCA cycle and 2HG. However, this effect on metabolism was not extended to viability; rather, our patient-derived IDH1 ^<i>mut</i> cell lines display a metabolic plasticity that allows them to overcome glutaminase inhibition.</p><p><strong>Conclusions: </strong>Major metabolic adaptations involved pathways that can generate glutamate by using alternative substrates from glutamine, such as alanine or aspartate. Indeed, asparagine synthetase was upregulated both in vivo and in vitro revealing a new potential therapeutic target for a combinatory approach with CB839 against IDH1 ^<i>mut</i> gliomas.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"8 ","pages":"23"},"PeriodicalIF":5.9,"publicationDate":"2020-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40170-020-00229-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38527972","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":"Modulating pyrimidine ribonucleotide levels for the treatment of cancer.","authors":"Tanzina Mollick,&nbsp;Sonia Laín","doi":"10.1186/s40170-020-00218-5","DOIUrl":"https://doi.org/10.1186/s40170-020-00218-5","url":null,"abstract":"<p><p>By providing the necessary building blocks for nucleic acids and precursors for cell membrane synthesis, pyrimidine ribonucleotides are essential for cell growth and proliferation. Therefore, depleting pyrimidine ribonucleotide pools has long been considered as a strategy to reduce cancer cell growth. Here, we review the pharmacological approaches that have been employed to modulate pyrimidine ribonucleotide synthesis and degradation routes and discuss their potential use in cancer therapy. New developments in the treatment of myeloid malignancies with inhibitors of pyrimidine ribonucleotide synthesis justify revisiting the literature as well as discussing whether targeting this metabolic pathway can be effective and sufficiently selective for cancer cells to warrant an acceptable therapeutic index in patients.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"8 ","pages":"12"},"PeriodicalIF":5.9,"publicationDate":"2020-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40170-020-00218-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38462307","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":"Disruption of redox homeostasis for combinatorial drug efficacy in <i>K-Ras</i> tumors as revealed by metabolic connectivity profiling.","authors":"Daniela Gaglio,&nbsp;Marcella Bonanomi,&nbsp;Silvia Valtorta,&nbsp;Rohit Bharat,&nbsp;Marilena Ripamonti,&nbsp;Federica Conte,&nbsp;Giulia Fiscon,&nbsp;Nicole Righi,&nbsp;Elisabetta Napodano,&nbsp;Federico Papa,&nbsp;Isabella Raccagni,&nbsp;Seth J Parker,&nbsp;Ingrid Cifola,&nbsp;Tania Camboni,&nbsp;Paola Paci,&nbsp;Anna Maria Colangelo,&nbsp;Marco Vanoni,&nbsp;Christian M Metallo,&nbsp;Rosa Maria Moresco,&nbsp;Lilia Alberghina","doi":"10.1186/s40170-020-00227-4","DOIUrl":"https://doi.org/10.1186/s40170-020-00227-4","url":null,"abstract":"<p><strong>Abstract: </strong></p><p><strong>Background: </strong>Rewiring of metabolism induced by oncogenic <i>K-Ras</i> in cancer cells involves both glucose and glutamine utilization sustaining enhanced, unrestricted growth. The development of effective anti-cancer treatments targeting metabolism may be facilitated by the identification and rational combinatorial targeting of metabolic pathways.</p><p><strong>Methods: </strong>We performed mass spectrometric metabolomics analysis in vitro and in vivo experiments to evaluate the efficacy of drugs and identify metabolic connectivity.</p><p><strong>Results: </strong>We show that <i>K-Ras</i>-mutant lung and colon cancer cells exhibit a distinct metabolic rewiring, the latter being more dependent on respiration. Combined treatment with the glutaminase inhibitor CB-839 and the PI3K/aldolase inhibitor NVP-BKM120 more consistently reduces cell growth of tumor xenografts. Maximal growth inhibition correlates with the disruption of redox homeostasis, involving loss of reduced glutathione regeneration, redox cofactors, and a decreased connectivity among metabolites primarily involved in nucleic acid metabolism.</p><p><strong>Conclusions: </strong>Our findings open the way to develop metabolic connectivity profiling as a tool for a selective strategy of combined drug repositioning in precision oncology.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"8 ","pages":"22"},"PeriodicalIF":5.9,"publicationDate":"2020-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40170-020-00227-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38541153","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":"Body mass index-associated molecular characteristics involved in tumor immune and metabolic pathways.","authors":"Chao Hu,&nbsp;Xiong Chen,&nbsp;Chengyun Yao,&nbsp;Yu Liu,&nbsp;Haojun Xu,&nbsp;Guoren Zhou,&nbsp;Hongping Xia,&nbsp;Jinglin Xia","doi":"10.1186/s40170-020-00225-6","DOIUrl":"https://doi.org/10.1186/s40170-020-00225-6","url":null,"abstract":"<p><strong>Background: </strong>Overweight or obesity has been evidenced as an important risk factor involved in the incidence, mortality, and therapy response of multiple malignancies. However, the differences between healthy and obesity tumor patients at the molecular and multi-omics levels remain unclear.</p><p><strong>Methods: </strong>Our study performed a comprehensive and multidimensional analysis in fourteen tumor types of The Cancer Genome Atlas (TCGA) and found body mass index (BMI)-related genes in multiple tumor types. Furthermore, we compared composite expression between normal, overweight, and obese patients of each immune cell subpopulation and metabolism gene subset. Statistical significance was calculated via the Kruskal-Wallis rank-sum test.</p><p><strong>Results: </strong>Our analysis revealed that BMI-related genes are enriched in multiple tumor-related biological pathways involved in intracellular signaling, immune response, and metabolism. We also found the different relationships between BMI and different immune cell infiltration and metabolic pathway activity. Importantly, we found that many clinically actionable genes were BMI-affect genes.</p><p><strong>Conclusion: </strong>Overall, our data indicated that BMI-associated molecular characteristics involved in tumor immune and metabolic pathways, which may highlight the clinical importance of considering BMI-associated molecular signatures in cancer precision medicine.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"8 ","pages":"21"},"PeriodicalIF":5.9,"publicationDate":"2020-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40170-020-00225-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38439376","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":"The conversion of formate into purines stimulates mTORC1 leading to CAD-dependent activation of pyrimidine synthesis.","authors":"Jacqueline Tait-Mulder, Kelly Hodge, David Sumpton, Sara Zanivan, Alexei Vazquez","doi":"10.1186/s40170-020-00228-3","DOIUrl":"10.1186/s40170-020-00228-3","url":null,"abstract":"<p><strong>Background: </strong>Mitochondrial serine catabolism to formate induces a metabolic switch to a hypermetabolic state with high rates of glycolysis, purine synthesis and pyrimidine synthesis. While formate is a purine precursor, it is not clear how formate induces pyrimidine synthesis.</p><p><strong>Methods: </strong>Here we combine phospho-proteome and metabolic profiling to determine how formate induces pyrimidine synthesis.</p><p><strong>Results: </strong>We discover that formate induces phosphorylation of carbamoyl phosphate synthetase (CAD), which is known to increase CAD enzymatic activity. Mechanistically, formate induces mechanistic target of rapamycin complex 1 (mTORC1) activity as quantified by phosphorylation of its targets S6, 4E-BP1, S6K1 and CAD. Treatment with the allosteric mTORC1 inhibitor rapamycin abrogates CAD phosphorylation and pyrimidine synthesis induced by formate. Furthermore, we show that the formate-dependent induction of mTOR signalling and CAD phosphorylation is dependent on an increase in purine synthesis.</p><p><strong>Conclusions: </strong>We conclude that formate activates mTORC1 and induces pyrimidine synthesis via the mTORC1-dependent phosphorylation of CAD.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"8 ","pages":"20"},"PeriodicalIF":5.9,"publicationDate":"2020-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38417301","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":"Metabolic plasticity imparts erlotinib-resistance in pancreatic cancer by upregulating glucose-6-phosphate dehydrogenase.","authors":"Neha Sharma,&nbsp;Alok Bhushan,&nbsp;Jun He,&nbsp;Gagan Kaushal,&nbsp;Vikas Bhardwaj","doi":"10.1186/s40170-020-00226-5","DOIUrl":"https://doi.org/10.1186/s40170-020-00226-5","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant forms of cancer. Lack of effective treatment options and drug resistance contributes to the low survival among PDAC patients. In this study, we investigated the metabolic alterations in pancreatic cancer cells that do not respond to the EGFR inhibitor erlotinib. We selected erlotinib-resistant pancreatic cancer cells from MiaPaCa2 and AsPC1 cell lines. Metabolic profiling of erlotinib-resistant cells revealed a significant downregulation of glycolytic activity and reduced level of glycolytic metabolites compared to the sensitive cells. The resistant cells displayed elevated expression of the pentose phosphate pathway (PPP) enzymes involved in ROS regulation and nucleotide biosynthesis. The enhanced PPP elevated cellular NADPH/NADP+ ratio and protected the cells from reactive oxygen species (ROS)-induced damage. Inhibition of PPP using 6-aminonicotinamide (6AN) elevated ROS levels, induced G1 cell cycle arrest, and sensitized resistant cells to erlotinib. Genetic studies identified elevated PPP enzyme glucose-6-phosphate dehydrogenase (G6PD) as an important contributor to erlotinib resistance. Mechanistically, our data showed that upregulation of inhibitor of differentiation (ID1) regulates G6PD expression in resistant cells thus contributing to altered metabolic phenotype and reduced response to erlotinib. Together, our results highlight an underlying role of tumor metabolism in PDAC drug response and identify G6PD as a target to overcome drug resistance.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"8 ","pages":"19"},"PeriodicalIF":5.9,"publicationDate":"2020-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40170-020-00226-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38417302","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":"A system for classifying cancers diagnosed in adolescents and young adults","authors":"Ronald D Barr, L. Ries, A. Trama, G. Gatta, E. Steliarova-Foucher, C. Stiller, W. Bleyer","doi":"10.2139/ssrn.3502376","DOIUrl":"https://doi.org/10.2139/ssrn.3502376","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"53 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2020-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81481005","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":"Correction to: Disruption of hypoxia-inducible fatty acid binding protein 7 induces beige fat-like differentiation and thermogenesis in breast cancer cells.","authors":"Masahiro Kawashima, Karim Bensaad, Christos E Zois, Alessandro Barberis, Esther Bridges, Simon Wigfield, Christoffer Lagerholm, Ruslan I Dmitriev, Mariko Tokiwa, Masakazu Toi, Dmitri B Papkovsky, Francesca M Buffa, Adrian L Harris","doi":"10.1186/s40170-020-00224-7","DOIUrl":"10.1186/s40170-020-00224-7","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1186/s40170-020-00219-4.].</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"8 ","pages":"18"},"PeriodicalIF":5.9,"publicationDate":"2020-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38259394","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":"Glutamine uptake and utilization of human mesenchymal glioblastoma in orthotopic mouse model.","authors":"Kristell Oizel, Chendong Yang, Ophelie Renoult, Fabien Gautier, Quyen N Do, Noemie Joalland, Xiaofei Gao, Bookyung Ko, François Vallette, Woo-Ping Ge, François Paris, Ralph J DeBerardinis, Claire Pecqueur","doi":"10.1186/s40170-020-00215-8","DOIUrl":"10.1186/s40170-020-00215-8","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma (GBM) are highly heterogeneous on the cellular and molecular basis. It has been proposed that glutamine metabolism of primary cells established from human tumors discriminates aggressive mesenchymal GBM subtype to other subtypes.</p><p><strong>Methods: </strong>To study glutamine metabolism in vivo, we used a human orthotopic mouse model for GBM. Tumors evolving from the implanted primary GBM cells expressing different molecular signatures were analyzed using mass spectrometry for their metabolite pools and enrichment in carbon 13 (¹³C) after ¹³C-glutamine infusion.</p><p><strong>Results: </strong>Our results showed that mesenchymal GBM tumors displayed increased glutamine uptake and utilization compared to both control brain tissue and other GBM subtypes. Furthermore, both glutamine synthetase and transglutaminase-2 were expressed accordingly to GBM metabolic phenotypes.</p><p><strong>Conclusion: </strong>Thus, our results outline the specific enhanced glutamine flux in vivo of the aggressive mesenchymal GBM subtype.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"8 ","pages":"9"},"PeriodicalIF":6.0,"publicationDate":"2020-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38259393","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":"Fumarate hydratase-deficient renal cell carcinoma cells respond to asparagine by activation of the unfolded protein response and stimulation of the hexosamine biosynthetic pathway.","authors":"Rony Panarsky,&nbsp;Daniel R Crooks,&nbsp;Andrew N Lane,&nbsp;Youfeng Yang,&nbsp;Teresa A Cassel,&nbsp;Teresa W-M Fan,&nbsp;W Marston Linehan,&nbsp;Jeffrey A Moscow","doi":"10.1186/s40170-020-00214-9","DOIUrl":"https://doi.org/10.1186/s40170-020-00214-9","url":null,"abstract":"<p><strong>Background: </strong>The loss-of-function mutation of fumarate hydratase (FH) is a driver of hereditary leiomyomatosis and renal cell carcinoma (HLRCC). Fumarate accumulation results in activation of stress-related mechanisms leading to upregulation of cell survival-related genes. To better understand how cells compensate for the loss of FH in HLRCC, we determined the amino acid nutrient requirements of the FH-deficient UOK262 cell line (UOK262) and its FH-repleted control (UOK262WT).</p><p><strong>Methods: </strong>We determined growth rates and survival of cell lines in response to amino acid depletion and supplementation. RNAseq was used to determine the transcription changes contingent on Asn and Gln supplementation, which was further followed with stable isotope resolved metabolomics (SIRM) using both [U- ¹³C,¹⁵N] Gln and Asn.</p><p><strong>Results: </strong>We found that Asn increased the growth rate of both cell lines in vitro. Gln, but not Asn, increased oxygen consumption rates and glycolytic reserve of both cell lines. Although Asn was taken up by the cells, there was little evidence of Asn-derived label in cellular metabolites, indicating that Asn was not catabolized. However, Asn strongly stimulated Gln labeling of uracil and precursors, uridine phosphates and hexosamine metabolites in the UOK262 cells and to a much lesser extent in the UOK262WT cells, indicating an activation of the hexosamine biosynthetic pathway (HBP) by Asn. Asn in combination with Gln, but not Asn or Gln alone, stimulated expression of genes associated with the endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in UOK262 to a greater extent than in FH-restored cells. The changes in expression of these genes were confirmed by RT-PCR, and the stimulation of the UPR was confirmed orthogonally by demonstration of an increase in spliced XBP1 (sXBP1) in UOK262 cells under these conditions. Asn exposure also increased both the RNA and protein expression of the HBP regulator GFPT2, which is a transcriptional target of sXBP1.</p><p><strong>Conclusions: </strong>Asn in the presence of Gln induces an ER stress response in FH-deficient UOK262 cells and stimulates increased synthesis of UDP-acetyl glycans indicative of HBP activity. These data demonstrate a novel effect of asparagine on cellular metabolism in FH-deficient cells that could be exploited therapeutically.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"8 ","pages":"7"},"PeriodicalIF":5.9,"publicationDate":"2020-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40170-020-00214-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38247830","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}