Multiple metabolic alterations exist in mutant PI3K cancers, but only glucose is essential as a nutrient source
Targeting tumour metabolism is becoming a major new area of pharmaceutical endeavour. Consequently, a systematic search to define whether there are specific energy source dependencies in tumours, and how these might be dictated by upstream driving genetic mutations, is required. The PI3K-AKT-mTOR si...
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| description | Targeting tumour metabolism is becoming a major new area of pharmaceutical endeavour. Consequently, a systematic search to define whether there are specific energy source dependencies in tumours, and how these might be dictated by upstream driving genetic mutations, is required. The PI3K-AKT-mTOR signalling pathway has a seminal role in regulating diverse cellular processes including cell proliferation and survival, but has also been associated with metabolic dysregulation. In this study, we sought to define how mutations within PI3KCA may affect the metabolic dependency of a cancer cell, using precisely engineered isogenic cell lines. Studies revealed gene expression signatures in PIK3CA mutant cells indicative of a consistent up-regulation of glycolysis. Interestingly, the genes up- and down-regulated varied between isogenic models suggesting that the primary node of regulation is not the same between models. Additional gene expression changes were also observed, suggesting that metabolic pathways other than glycolysis, such as glutaminolysis, were also affected. Nutrient dependency studies revealed that growth of PIK3CA mutant cells is highly dependent on glucose, whereas glutamine dependency is independent of PIK3CA status. In addition, the glucose dependency exhibited by PIK3CA mutant cells could not be overridden by supplementation with other nutrients. This specific dependence on glucose for growth was further illustrated by studies evaluating the effects of targeted disruption of the glycolytic pathway using siRNA and was also found to be present across a wider panel of cancer cell lines harbouring endogenous PIK3CA mutations. In conclusion, we have found that PIK3CA mutations lead to a shift towards a highly glycolytic phenotype, and that despite suggestions that cancer cells are adept at utilising alternative nutrient sources, PIK3CA mutant cells are not able to compensate for glucose withdrawal. Understanding the metabolic dependencies of PIK3CA mutant cancers will provide critical information for the design of effective therapies and tumour visualisation strategies. |
| doi_str_mv | 10.1371/journal.pone.0045061 |
| format | Article |
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Consequently, a systematic search to define whether there are specific energy source dependencies in tumours, and how these might be dictated by upstream driving genetic mutations, is required. The PI3K-AKT-mTOR signalling pathway has a seminal role in regulating diverse cellular processes including cell proliferation and survival, but has also been associated with metabolic dysregulation. In this study, we sought to define how mutations within PI3KCA may affect the metabolic dependency of a cancer cell, using precisely engineered isogenic cell lines. Studies revealed gene expression signatures in PIK3CA mutant cells indicative of a consistent up-regulation of glycolysis. Interestingly, the genes up- and down-regulated varied between isogenic models suggesting that the primary node of regulation is not the same between models. Additional gene expression changes were also observed, suggesting that metabolic pathways other than glycolysis, such as glutaminolysis, were also affected. Nutrient dependency studies revealed that growth of PIK3CA mutant cells is highly dependent on glucose, whereas glutamine dependency is independent of PIK3CA status. In addition, the glucose dependency exhibited by PIK3CA mutant cells could not be overridden by supplementation with other nutrients. This specific dependence on glucose for growth was further illustrated by studies evaluating the effects of targeted disruption of the glycolytic pathway using siRNA and was also found to be present across a wider panel of cancer cell lines harbouring endogenous PIK3CA mutations. In conclusion, we have found that PIK3CA mutations lead to a shift towards a highly glycolytic phenotype, and that despite suggestions that cancer cells are adept at utilising alternative nutrient sources, PIK3CA mutant cells are not able to compensate for glucose withdrawal. Understanding the metabolic dependencies of PIK3CA mutant cancers will provide critical information for the design of effective therapies and tumour visualisation strategies.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0045061</identifier><identifier>PMID: 23028762</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>1-Phosphatidylinositol 3-kinase ; AKT protein ; Amino acids ; Biology ; Biotechnology ; Breast cancer ; Cancer ; Cancer research ; Cell cycle ; Cell growth ; Cell Line, Tumor ; Cell proliferation ; Cell Proliferation - drug effects ; Cell survival ; Class I Phosphatidylinositol 3-Kinases ; Cytotoxicity ; Enzyme Activation - drug effects ; Fatty acids ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic - drug effects ; Gene mutation ; Gene Targeting ; Genes ; Genetic aspects ; Glucose ; Glucose - metabolism ; Glucose - pharmacology ; Glutamine ; Glutamine - metabolism ; Glutamine - pharmacology ; Glycolysis ; Glycolysis - drug effects ; Glycolysis - genetics ; Humans ; Kinases ; Medicine ; Metabolic pathways ; Metabolism ; Metabolome - drug effects ; Metabolome - genetics ; Metastasis ; Mutant Proteins - metabolism ; Mutation ; Mutation - genetics ; Neoplasms - enzymology ; Neoplasms - genetics ; Neoplasms - metabolism ; Neoplasms - pathology ; Nutrient sources ; Nutrients ; Oxidation ; Phenotypes ; Phosphatidylinositol 3-Kinases - genetics ; Phosphatidylinositol 3-Kinases - metabolism ; Prostate cancer ; Signal transduction ; Signaling ; siRNA ; Supplements ; TOR protein ; Tumor cell lines ; Tumors ; Up-Regulation - drug effects ; Up-Regulation - genetics ; Warburg, Otto</subject><ispartof>PloS one, 2012-09, Vol.7 (9), p.e45061</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>Foster et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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Consequently, a systematic search to define whether there are specific energy source dependencies in tumours, and how these might be dictated by upstream driving genetic mutations, is required. The PI3K-AKT-mTOR signalling pathway has a seminal role in regulating diverse cellular processes including cell proliferation and survival, but has also been associated with metabolic dysregulation. In this study, we sought to define how mutations within PI3KCA may affect the metabolic dependency of a cancer cell, using precisely engineered isogenic cell lines. Studies revealed gene expression signatures in PIK3CA mutant cells indicative of a consistent up-regulation of glycolysis. Interestingly, the genes up- and down-regulated varied between isogenic models suggesting that the primary node of regulation is not the same between models. Additional gene expression changes were also observed, suggesting that metabolic pathways other than glycolysis, such as glutaminolysis, were also affected. 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Consequently, a systematic search to define whether there are specific energy source dependencies in tumours, and how these might be dictated by upstream driving genetic mutations, is required. The PI3K-AKT-mTOR signalling pathway has a seminal role in regulating diverse cellular processes including cell proliferation and survival, but has also been associated with metabolic dysregulation. In this study, we sought to define how mutations within PI3KCA may affect the metabolic dependency of a cancer cell, using precisely engineered isogenic cell lines. Studies revealed gene expression signatures in PIK3CA mutant cells indicative of a consistent up-regulation of glycolysis. Interestingly, the genes up- and down-regulated varied between isogenic models suggesting that the primary node of regulation is not the same between models. Additional gene expression changes were also observed, suggesting that metabolic pathways other than glycolysis, such as glutaminolysis, were also affected. Nutrient dependency studies revealed that growth of PIK3CA mutant cells is highly dependent on glucose, whereas glutamine dependency is independent of PIK3CA status. In addition, the glucose dependency exhibited by PIK3CA mutant cells could not be overridden by supplementation with other nutrients. This specific dependence on glucose for growth was further illustrated by studies evaluating the effects of targeted disruption of the glycolytic pathway using siRNA and was also found to be present across a wider panel of cancer cell lines harbouring endogenous PIK3CA mutations. In conclusion, we have found that PIK3CA mutations lead to a shift towards a highly glycolytic phenotype, and that despite suggestions that cancer cells are adept at utilising alternative nutrient sources, PIK3CA mutant cells are not able to compensate for glucose withdrawal. Understanding the metabolic dependencies of PIK3CA mutant cancers will provide critical information for the design of effective therapies and tumour visualisation strategies.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23028762</pmid><doi>10.1371/journal.pone.0045061</doi><tpages>e45061</tpages><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1326544739 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | 1-Phosphatidylinositol 3-kinase AKT protein Amino acids Biology Biotechnology Breast cancer Cancer Cancer research Cell cycle Cell growth Cell Line, Tumor Cell proliferation Cell Proliferation - drug effects Cell survival Class I Phosphatidylinositol 3-Kinases Cytotoxicity Enzyme Activation - drug effects Fatty acids Gene expression Gene Expression Profiling Gene Expression Regulation, Neoplastic - drug effects Gene mutation Gene Targeting Genes Genetic aspects Glucose Glucose - metabolism Glucose - pharmacology Glutamine Glutamine - metabolism Glutamine - pharmacology Glycolysis Glycolysis - drug effects Glycolysis - genetics Humans Kinases Medicine Metabolic pathways Metabolism Metabolome - drug effects Metabolome - genetics Metastasis Mutant Proteins - metabolism Mutation Mutation - genetics Neoplasms - enzymology Neoplasms - genetics Neoplasms - metabolism Neoplasms - pathology Nutrient sources Nutrients Oxidation Phenotypes Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositol 3-Kinases - metabolism Prostate cancer Signal transduction Signaling siRNA Supplements TOR protein Tumor cell lines Tumors Up-Regulation - drug effects Up-Regulation - genetics Warburg, Otto |
| title | Multiple metabolic alterations exist in mutant PI3K cancers, but only glucose is essential as a nutrient source |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-12T21%3A25%3A12IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Multiple%20metabolic%20alterations%20exist%20in%20mutant%20PI3K%20cancers,%20but%20only%20glucose%20is%20essential%20as%20a%20nutrient%20source&rft.jtitle=PloS%20one&rft.au=Foster,%20Rebecca&rft.date=2012-09-13&rft.volume=7&rft.issue=9&rft.spage=e45061&rft.pages=e45061-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0045061&rft_dat=%3Cgale_plos_%3EA543317628%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1326544739&rft_id=info:pmid/23028762&rft_galeid=A543317628&rft_doaj_id=oai_doaj_org_article_834d1b4441a949d0bfb401466e5229ca&rfr_iscdi=true |