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

Abstract

Mitochondrial 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.

Pregnancy-associated plasma protein-aa promotes neuron survival by regulating mitochondrial function

“…Here, we define a novel role for Pappaa in neuron survival by stimulating the IGF1 signaling pathway and regulating mitochondrial function. The evidence we present is consistent with demonstrations that IGF1 regulates neuron survival and mitochondrial function (Zheng et al, 2000; Luo et al, 2003; García-Fernández et al, 2008; Lyons et al, 2017). Our discovery of Pappaa in this context breathes hope into the potential for IGF1 mediated therapies for neurodegenerative diseases.…”

“…The mitochondria in pappaa p170 mutant hair cells showed multiple signs of dysfunction, including elevated ROS (Fig 4c-f), transmembrane potential (Fig 5c-d), and Ca 2 + load (Fig 5a-b). Consistent with these observations, reduced IGF1 signaling has been associated with increased ROS production and oxidative stress (García-Fernández et al, 2008; Lyons et al, 2017). Two lines of evidence suggest that mitochondrial dysfunction, and particularly the elevated ROS production, underlie neuron loss in pappaa p170 mutants.…”

“…The insulin-like growth factor-1 (IGF1) signaling pathway is known to affect a neuron’s mitochondrial function and its survival. Inhibition of IGF1 signaling causes loss of hippocampal neurons (Luo et al, 2003) and reduced IGF1 signaling has been shown to disrupt mitochondrial function, biogenesis, and ROS production (Lyons et al, 2017). Such mitochondrial defects are detrimental to neuron survival (Schon and Manfredi, 2003; Golpich et al, 2017).…”

Construction of a set of novel and robust gene expression signatures predicting prostate cancer recurrence

“…Five genes CGNL1, SUPV3L1, TATDN2, CASKIN1, and GOLGA7B are of unknown functions in either prostate cancer tumorigenesis or tumorigenesis in general (Table 1). Six genes (SLCO2A1, MGAT4B, SLC25A33, MCCC1, OIP5, and CTHRC1) have been shown to affect the tumorigenesis of other cancer types but not PC (Blomme et al, 2013;Chen et al, 2013;Guda et al, 2014;Ke et al, 2014;Lyons et al, 2017;Ribeiro et al, 2014;Tarnowski et al, 2016) (Table 1). OIP5 (Opa interacting protein 5) is a cancer testis antigen and has been reported in other cancer types as a type of tumor-associated antigen (TAA) (Tarnowski et al, 2016); its detection in PC here suggests OIP5 being a TAA for PC.…”

From fever to immunity: A new role for IGFBP‐6?

“…However, although IGFs exert an established control on glucose and lipid homeostasis as well as a net anabolic effect on protein metabolism, the molecular mechanisms of their actions are not completely understood. Recent evidences suggest the involvement of the IGF‐IR‐mediated signalling in preserving the mitochondrial structure and function achieved by controlling mitochondrial biogenesis and mitophagy as well as reactive oxygen species homeostasis 55, 56. In addition to IGFs‐related effects, IGFBPs proved to activate directly receptor‐mediated signaling pathways (see ahead).…”