Insulin-like Growth Factor-1 signalling is essential for mitochondrial protection in cancer cells
Sarah Riis1, Amy Lyons1, Michael Coleman1, 2, Cedric Favre1, Ciara H. O'Flanagan2,
Stephen D. Hursting2, and Rosemary O'Connor1
School of Biochemistry and Cell Biology, University College Cork, Ireland; 2Division of Nutritional Biochemistry, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, USA
Mitochondrial activity and cellular metabolic reprogramming may influence the phenotype of cancer cells and mediate resistance to targeted therapy. Previously, we reported that an IGF-1-inducible mitochondrial carrier protein for nucleotides (PNC1/SLC25A33) is essential for maintenance of mitochondria and cell growth1, 2. This suggested an underlying role for IGF-1 signalling in mitochondrial homeostasis. To explore this further we investigated the signalling pathways by which IGF-1 promotes mitochondrial maintenance.
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 wide range of cell lines3. This response requires both PGC-1β and PRC, and their suppression with siRNA is sufficient to reduce mitochondrial mass, and to disrupt mitochondrial morphology and membrane potential. Moreover, IGF-1 induces expression and mitochondrial accumulation of the mitophagy receptor BNIP3, as well as the Nrf2/NFE2L2 gene, which has been implicated in both mitochondrial biogenesis and anti-oxidant responses. Interestingly, suppression of Nrf2 with siRNA caused reduced induction of BNIP3 in response to IGF-1, suggesting a role for Nrf2 and in integrating IGF-1-mediated regulation of mitophagy with survival and metabolic reprogramming in cancer cells.
Overall we conclude that IGF-1 signalling has an essential function in mitochondria function, stimulating biogenesis and turnover. This mitochondria protective signal is likely to strongly influence responses to therapy and the phenotypic evolution of cancer.
- 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.
- Favre, C., et al; (2010) Pyrimidine Nucleotide Carrier (PNC1) regulates mitochondrial biogenesis and the invasive phenotype of cancer cells. Oncogene 29:3964-3976.
- Lyons, A. et al. (2017) IGF-1- signalling is essential for mitochondrial biogenesis and mitophagy in cancer cells. J. Biol. Chem. 292:16983-16998.