Lyons Amy, Coleman Michael, Riis Sarah, Favre Cedric, O'Flanagan Ciara H, Zhdanov Alexander V, Papkovsky Dmitri B, Hursting Stephen D, O'Connor Rosemary
From the Cell Biology Laboratory and.
the Division of Nutritional Biochemistry, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7400.
J Biol Chem. 2017 Oct 13;292(41):16983-16998. doi: 10.1074/jbc.M117.792838. Epub 2017 Aug 18.
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.
线粒体活性和代谢重编程影响癌细胞的表型及对靶向治疗的抗性。我们之前证实，胰岛素样生长因子1（IGF-1）诱导的线粒体UTP载体（PNC1/SLC25A33）可促进细胞生长。这促使我们研究IGF信号传导对于癌细胞中线粒体维持是否必不可少，以及这是否会导致治疗抗性。在此我们表明，IGF-1可刺激一系列细胞系中的线粒体生物合成。在MCF-7和ZR75.1乳腺癌细胞中，IGF-1诱导过氧化物酶体增殖物激活受体γ共激活因子1β（PGC-1β）和PGC-1α相关共激活因子（PRC）。用小干扰RNA（siRNA）抑制PGC-1β和PRC可逆转IGF-1的作用，并破坏线粒体形态和膜电位。IGF-1还诱导氧化还原调节因子核因子红细胞衍生2样2（NFE2L2，别名NRF-2）的表达。值得注意的是，对IGF-1受体（IGF-1R）酪氨酸激酶抑制剂产生获得性抗性的MCF-7细胞，其PGC-1β、PRC和线粒体生物合成的表达降低。有趣的是，这些细胞表现出线粒体功能障碍，表现为活性氧表达、线粒体自噬介质BNIP3和BNIP3L表达降低以及线粒体自噬受损。与此一致的是，IGF-1强烈诱导BNIP3在线粒体中的积累。其他活性受体酪氨酸激酶无法补偿IGF-1R活性降低对线粒体的保护作用，且IGF-1R活性受到抑制的MCF-7细胞对糖酵解的依赖性增强以维持生存。我们得出结论，IGF-1信号传导通过刺激线粒体生物合成和通过诱导BNIP3进行周转，对于维持癌细胞活力至关重要。这种核心的线粒体保护信号可能会强烈影响对治疗的反应以及癌症的表型演变。
