ERRα Maintains Mitochondrial Oxidative Metabolism and Constitutes an Actionable Target in PGC1α- Elevated Melanomas

The uncontrolled growth of tumors provides metabolic dependencies that can be harnessed for therapeutic benefit. Although tumor cells exhibit these increased metabolic demands due to their rapid proliferation, these metabolic processes are general to all cells, and furthermore, targeted therapeutic intervention can provoke compensatory adaptation that alters tumors' characteristics. As an example, a subset of melanomas depends on the transcriptional coactivator PGC1 alpha function to sustain their mitochondrial energy-dependent survival. However, selective outgrowth of resistant PGC1 alpha-independent tumor cells becomes endowed with an augmented metastatic phenotype. To find PGC1 alpha-dependent components that would not affect metastasis in melanomas, an unbiased proteomic analyses was performed and uncovered the orphan nuclear receptor ERR alpha, which supports PGC1 alpha's control of mitochondrial energetic metabolism, but does not affect the antioxidant nor antimetastatic regulatory roles. Specifically, genetic or pharmacologic inhibition of ERR alpha reduces the inherent bioenergetic capacity and decreases melanoma cell growth, but without altering the invasive characteristics. Thus, within this particularly aggressive subset of melanomas, which is characterized by heighted expression of PGC1 alpha, ERR alpha specifically mediates prosurvival functions and represents a tangible therapeutic target. (C) 2017 AACR.