Insulin-like growth factor-1 signaling promotes mitochondrial turnover and protection in cancer cells

Mitochondrial activity and cellular metabolic reprogramming may influence cancer phenotype and contribute to therapy resistance. Our previous work showed that Insulin-like Growth Factor 1 (IGF-1) induces expression of a mitochondrial carrier protein for nucleotides (PNC1/SLC25A33). PNC1 has an essential function in maintenance of mitochondrial RNA, DNA and in cell growth 1, 2. This suggested an underlying role for IGF-1 signalling in mitochondrial homeostasis. To explore this further we investigated (1) the signalling pathways by which IGF-1 promotes mitochondrial maintenance, and (2) investigated whether PNC1 expression levels influence the phenotype of cancer cells. We found that activation of the IGF-1 pathway promotes mitochondrial biogenesis through induction of the transcriptional co-activators PGC-1β and PRC in a range of cell lines3. MCF-7 breast cancer cells with acquired resistance to an IGF-1R tyrosine kinase inhibitor and consequently reduced IGF-1R activity (MCF-7R cells) exhibit lower expression of PGC-1β and PRC and impaired mitochondrial biogenesis compared to controls3. Interestingly, MCF-7R cells also exhibit mitochondrial dysfunction and a strong dependence on glycolysis for survival. IGF-1 also induces expression of the Nrf2/NFE2L2 gene, which is implicated in mitochondrial biogenesis, anti-oxidant responses, and regulating expression of the mitophagy mediator BNIP3. Interestingly, suppression of Nrf2 impaired the induction of BNIP3 in response to IGF-1. This suggests that Nrf2 integrates IGF-1-stimulated mitochondrial biogenesis with induction of mitophagy to regulate mitochondrial turnover and promote the survival of cancer cells. To investigate the role of IGF-1-induced PNC1 in cancer cell metabolism we manipulated its expression in different cell lines. PNC1 suppression was associated with loss of cell growth, acquisition of an invasive phenotype, and impaired mitochondrial function indicated by reduced respiration. Ectopic expression of PNC1 was sufficient to restore mitochondrial function, and to suppress clonogenic growth and invasive characteristics. Overall we conclude that IGF-1 signalling protects mitochondrial function in cancer cells by stimulating biogenesis and turnover. This mitochondria protective signal is likely to strongly influence responses to therapy and the phenotypic evolution of cancer. References: 1. Floyd, S. et al (2007) The Insulin-like Growth Factor-I mTOR Signaling Pathway Induces the Mitochondrial Pyrimidine Nucleotide Carrier to Promote Cell Growth Mol. Biol Cell. 18:3545-3555. 2. Favre, C. et al (2010) Pyrimidine Nucleotide Carrier (PNC1) regulates mitochondrial biogenesis and the invasive phenotype of cancer cells. Oncogene 29:3964-3976. 3. Lyons, A. et al (2017) IGF-1- signalling is essential for mitochondrial biogenesis and mitophagy in cancer cells. J. Biol. Chem. 292:16983-16998. Citation Format: Sarah Riis, Michael Coleman, Stephen D. Hursting, Rosemary O9Connor. Insulin-like growth factor-1 signaling promotes mitochondrial turnover and protection in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2718.