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

Overview of attention for article published in Journal of Biological Chemistry, October 2017
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Title
Insulin-like growth factor 1 signaling is essential for mitochondrial biogenesis and mitophagy in cancer cells
Published in
Journal of Biological Chemistry, October 2017
DOI 10.1074/jbc.m117.792838
Pubmed ID
Authors

Amy Lyons, Michael Coleman, Sarah Riis, Cedric Favre, Ciara H. O'Flanagan, Alexander V. Zhdanov, Dmitri B. Papkovsky, Stephen D. Hursting, Rosemary O'Connor

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 gamma 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-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 (ROS) expression, reduced expression of 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.

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Mendeley readers

The data shown below were compiled from readership statistics for 75 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 75 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 20 27%
Student > Master 13 17%
Researcher 7 9%
Student > Bachelor 6 8%
Student > Postgraduate 4 5%
Other 8 11%
Unknown 17 23%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 27 36%
Agricultural and Biological Sciences 13 17%
Medicine and Dentistry 6 8%
Neuroscience 3 4%
Immunology and Microbiology 2 3%
Other 3 4%
Unknown 21 28%