Insulin-like growth factor 1 effects on mitochondrial dynamics and mitophagy in cancer

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Riis, Sarah
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University College Cork
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The evolutionarily conserved Insulin-Like Growth Factor 1 (IGF-1) signalling pathway is essential for growth and development and may facilitate cancer progression. While IGF-1 mediates mitochondria protection in some pathologies, whether it is essential for mitochondrial homeostasis in tumour cells remains mostly unknown. Mitochondria are key organelles for energy production, and, therefore, cancer cells rely on mitochondrial maintenance to support rapid cell proliferation. In this thesis, the effects of IGF-1 signalling on mitochondrial biogenesis, dynamics and turnover in cancer cells were investigated. IGF-1 signalling was shown to promote mitochondrial biogenesis by inducing Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) Coactivator-1 β (PGC-1β) and PGC-1-Related Coactivator (PRC) to promote mitochondrial biogenesis, while also inducing the mitophagy receptor B-cell Lymphoma 2 (BCL-2)/Adenovirus E1B 19 kDa Protein-Interacting Protein 3 (BNIP3). IGF-1 also activated the transcriptional regulator Nuclear Factor, Erythroid 2 Like 2 (NFE2L2/Nrf2), likely through inactivation of Glycogen Synthase 3β (GSK-3β). Both Nrf2 and Hypoxia-Inducible Factor 1α (HIF-1α) were required for IGF-1-mediated induction of BNIP3. While BNIP3 apparently inhibited cellular macro-autophagy, it facilitated mitophagy in cancer cells in response to a range of stimuli. A mitophagy reporter (pcDNA3.1-VLCAD(1-40)-mCherry-EGFP) was generated and tested to allow direct visualisation and quantification of cellular mitophagy. Unexpectedly, this reporter indicated that IGF-1 suppresses overall mitophagy in serum-deprived cell cultures. However, IGF-1 also induced colocalisation of BNIP3 with EGFP-LC3 in these cells, demonstrating that IGF-1 signalling selectively activates BNIP3-mediated mitophagy. The importance of IGF-1 signalling in mitochondrial turnover was further demonstrated in IGF-1 receptor null mouse embryonic fibroblasts (R- cells) and these cells re-constituted with the IGF-1 receptor (R+ cells). Compared to R+ cells, R- cells exhibited impaired mitophagic clearance and reduced cell survival in response to mitochondrial stress. Overall the findings of the thesis demonstrate that IGF-1 signalling enhances mitochondria health to support cellular robustness. This basal IGF-1 signal enhances mitophagy while also supressing macro autophagy, thus providing a critical mitochondrial protection signal. In cancer, this could be exploited therapeutically by co-targeting the IGF-1R with other therapies to generate mitochondrial vulnerabilities that would limit cancer progression.
Cancer , IGF-1 , Mitochondria , Mitophagy , NFE2L2 , BNIP3
Riis, S. 2020. Insulin-like growth factor 1 effects on mitochondrial dynamics and mitophagy in cancer. PhD Thesis, University College Cork.
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