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

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dc.contributor.authorLyons, Amy
dc.contributor.authorColeman, Michael
dc.contributor.authorRiis, Sarah
dc.contributor.authorFavre, Cedric
dc.contributor.authorO'Flanagan, Ciara
dc.contributor.authorZhdanov, Alexander V.
dc.contributor.authorPapkovsky, Dmitri B.
dc.contributor.authorHursting, Stephen D.
dc.contributor.authorO'Connor, Rosemary
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderHealth Research Boarden
dc.contributor.funderHigher Education Authorityen
dc.contributor.funderIrish Cancer Societyen
dc.date.accessioned2018-01-12T11:34:43Z
dc.date.available2018-01-12T11:34:43Z
dc.date.issued2017-08-18
dc.date.updated2018-01-12T11:13:14Z
dc.description.abstractMitochondrial 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.sponsorshipHigher Education Authority (Ph.D. Program in Molecular Cell Biology); Irish Cancer Society (Ph.D. Studentship)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationLyons, 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.M117.792838en
dc.identifier.doi10.1074/jbc.M117.792838
dc.identifier.endpage16998en
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.issued41en
dc.identifier.journaltitleJournal of Biological Chemistryen
dc.identifier.startpage16983en
dc.identifier.urihttps://hdl.handle.net/10468/5270
dc.identifier.volume292en
dc.language.isoenen
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Principal Investigator Programme (PI)/11/PI/1139/IE/IGF-I Receptor signalling and regulation/en
dc.relation.projectinfo: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
dc.rights© 2017, the American Society for Biochemistry and Molecular Biology, Inc.en
dc.subjectCancer biologyen
dc.subjectCancer therapyen
dc.subjectCell metabolismen
dc.subjectCell signalingen
dc.subjectCell surface receptoren
dc.subjectDrug resistanceen
dc.subjectInsulin-like growth factoren
dc.subjectIGFen
dc.subjectMitochondriaen
dc.subjectMitophagyen
dc.titleInsulin-like growth factor 1 signaling is essential for mitochondrial biogenesis and mitophagy in cancer cellsen
dc.typeArticle (peer-reviewed)en
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