Abstract
The Insulin-like Growth Factor I (IGF-1) signalling pathway is essential for cell growth and facilitates tumourogenic processes. We recently reported that IGF-1 induces a transcriptional programme for mitochondrial biogenesis, while also inducing expression of the mitophagy receptor BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), suggesting that IGF-1 has a key mitochondria-protective role in cancer cells. Here, we investigated this further and delineated the signaling pathway for BNIP3 induction. We established that IGF-1 induced BNIP3 expression through a known AKT serine/threonine kinase 1 (AKT)-mediated inhibitory phosphorylation on Glycogen Synthase Kinase-3β (GSK-3β), leading to activation of Nuclear Factor Erythroid 2-related Factor 2 (NFE2L2/Nrf2) and acting through the downstream transcriptional regulators Nuclear Respiratory Factor-1 (NRF1) and Hypoxia-inducible Factor 1 subunit α (HIF-1α). Suppression of IGF-1 signaling, Nrf2 or BNIP3 caused the accumulation of elongated mitochondria and altered the mitochondrial dynamics. IGF-1R null Mouse Embryonic Fibroblasts (MEFs) were impaired in the BNIP3 expression and in the capacity to mount a cell survival response in response to serum deprivation or mitochondrial stress. IGF-1 signalling enhanced the cellular capacity to induce autophagosomal turnover in response to activation of either general autophagy or mitophagy. Overall, we conclude that IGF-1 mediated a mitochondria-protective signal that was coordinated through the cytoprotective transcription factor Nrf2. This pathway coupled mitochondrial biogenesis with BNIP3 induction, and increased the cellular capacity for autophagosome turnover, whilst enhancing survival under conditions of metabolic or mitochondrial stress.
Highlights
The IGF-1 signalling pathway is essential for cell growth and survival [1], and has the potential to enhance tumourigenesis and cancer progression [2,3]
Since mitochondrial biogenesis and mitophagy may be coupled, and since Nrf2 promotes the transcription of the BCL2/adenovirus E1B kDa protein-interacting protein 3 (BNIP3)/NIX orthologue
IGF-1 signalling is essential for growth and promotes tumourigenesis, cancer cell survival and proliferation, as well as having a highly conserved and potent effect on mitochondrial function and homeostasis [1,2,9]
Summary
The IGF-1 signalling pathway is essential for cell growth and survival [1], and has the potential to enhance tumourigenesis and cancer progression [2,3]. The compelling evidence for IGF actions in cancer and its central function in human biology and ageing mean that it is important to better understand the mechanisms and regulation of this signalling pathway such that it may be successfully modulated or targeted for therapeutic benefit. Mitochondrial dysfunction is a common feature of cancer cells that may arise due to altered fusion/fission dynamics, oxidative stress, metabolic reprogramming and other mitochondrial changes, as reviewed by Vyas and Haigis [6]. Emerging evidence suggests that dysregulation of mitophagy is common in cancer, and that the accumulation of dysfunctional mitochondria drives cancer. It has been proposed that mitophagy and mitochondrial biogenesis are uncoupled in cancer due to the observed upregulation in mitochondrial biogenesis associated with downregulation of mitophagy [7]
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