Insulin-like growth factor 1 signaling is essential for mitochondrial biogenesis and mitophagy in cancer cells

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dc.contributor.author Lyons, Amy
dc.contributor.author Coleman, Michael
dc.contributor.author Riis, Sarah
dc.contributor.author Favre, Cedric
dc.contributor.author O'Flanagan, Ciara
dc.contributor.author Zhdanov, Alexander V.
dc.contributor.author Papkovsky, Dmitri B.
dc.contributor.author Hursting, Stephen D.
dc.contributor.author O'Connor, Rosemary
dc.date.accessioned 2018-01-12T11:34:43Z
dc.date.available 2018-01-12T11:34:43Z
dc.date.issued 2017-08-18
dc.identifier.citation Lyons, A., Coleman, M., Riis, S., Favre, C., O'Flanagan, C. H., Zhdanov, A. V., Papkovsky, D. B., Hursting, S. D. and O'Connor, R. (2017) 'Insulin-like growth factor 1 signaling is essential for mitochondrial biogenesis and mitophagy in cancer cells', Journal of Biological Chemistry, 292(41), pp. 16983-16998. doi:10.1074/jbc.M117.792838 en
dc.identifier.volume 292 en
dc.identifier.issued 41 en
dc.identifier.startpage 16983 en
dc.identifier.endpage 16998 en
dc.identifier.issn 0021-9258
dc.identifier.issn 1083-351X
dc.identifier.uri http://hdl.handle.net/10468/5270
dc.identifier.doi 10.1074/jbc.M117.792838
dc.description.abstract Mitochondrial activity and metabolic reprogramming influence the phenotype of cancer cells and resistance to targeted therapy. We previously established that an insulin-like growth factor 1 (IGF-1)-inducible mitochondrial UTP carrier (PNC1/SLC25A33) promotes cell growth. This prompted us to investigate whether IGF signaling is essential for mitochondrial maintenance in cancer cells and whether this contributes to therapy resistance. Here we show that IGF-1 stimulates mitochondrial biogenesis in a range of cell lines. In MCF-7 and ZR75.1 breast cancer cells, IGF-1 induces peroxisome proliferator–activated receptor γ coactivator 1β (PGC-1β) and PGC-1α–related coactivator (PRC). Suppression of PGC-1β and PRC with siRNA reverses the effects of IGF-1 and disrupts mitochondrial morphology and membrane potential. IGF-1 also induced expression of the redox regulator nuclear factor-erythroid-derived 2-like 2 (NFE2L2 alias NRF-2). Of note, MCF-7 cells with acquired resistance to an IGF-1 receptor (IGF-1R) tyrosine kinase inhibitor exhibited reduced expression of PGC-1β, PRC, and mitochondrial biogenesis. Interestingly, these cells exhibited mitochondrial dysfunction, indicated by reactive oxygen species expression, reduced expression of the mitophagy mediators BNIP3 and BNIP3L, and impaired mitophagy. In agreement with this, IGF-1 robustly induced BNIP3 accumulation in mitochondria. Other active receptor tyrosine kinases could not compensate for reduced IGF-1R activity in mitochondrial protection, and MCF-7 cells with suppressed IGF-1R activity became highly dependent on glycolysis for survival. We conclude that IGF-1 signaling is essential for sustaining cancer cell viability by stimulating both mitochondrial biogenesis and turnover through BNIP3 induction. This core mitochondrial protective signal is likely to strongly influence responses to therapy and the phenotypic evolution of cancer. en
dc.description.sponsorship Higher Education Authority (Ph.D. Program in Molecular Cell Biology); Irish Cancer Society (Ph.D. Studentship) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher American Society for Biochemistry and Molecular Biology en
dc.rights © 2017, the American Society for Biochemistry and Molecular Biology, Inc. en
dc.subject Cancer biology en
dc.subject Cancer therapy en
dc.subject Cell metabolism en
dc.subject Cell signaling en
dc.subject Cell surface receptor en
dc.subject Drug resistance en
dc.subject Insulin-like growth factor en
dc.subject IGF en
dc.subject Mitochondria en
dc.subject Mitophagy en
dc.title Insulin-like growth factor 1 signaling is essential for mitochondrial biogenesis and mitophagy in cancer cells en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother Dmitri Papkovsky, School Of Biochemistry & Cell Biology, University College Cork, Cork, Ireland. +353-21-490-3000 Email: d.papkovsky@ucc.ie en
dc.internal.availability Full text available en
dc.check.info Access to this article is restricted until 12 months after publication by request of the publisher. en
dc.check.date 2018-08-18
dc.date.updated 2018-01-12T11:13:14Z
dc.description.version Published Version en
dc.internal.rssid 421497167
dc.contributor.funder Science Foundation Ireland en
dc.contributor.funder Health Research Board en
dc.contributor.funder Higher Education Authority en
dc.contributor.funder Irish Cancer Society en
dc.description.status Peer reviewed en
dc.identifier.journaltitle Journal of Biological Chemistry en
dc.internal.copyrightchecked Yes en
dc.internal.licenseacceptance Yes en
dc.internal.IRISemailaddress d.papkovsky@ucc.ie en
dc.relation.project info:eu-repo/grantAgreement/SFI/SFI Principal Investigator Programme (PI)/11/PI/1139/IE/IGF-I Receptor signalling and regulation/ en
dc.relation.project info:eu-repo/grantAgreement/SFI/SFI Principal Investigator Programme (PI)/06/IN.1/B107/IE/The IGF-IR Signalling Pathway in Tumour Cells: A Study of Two New Proteins/ en


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