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

Abstract

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 PGC1α function to sustain their mitochondrial energy-dependent survival. However, selective outgrowth of resistant PGC1α-independent tumor cells becomes endowed with an augmented metastatic phenotype. To find PGC1α−dependent components that would not affect metastasis in melanomas, an unbiased proteomic analyses was performed and uncovered the orphan nuclear receptor ERRα, which supports PGC1α’s control of mitochondrial energetic metabolism, but does not affect the anti-oxidant nor anti-metastatic regulatory roles. Specifically, genetic or pharmacologic inhibition of ERRα 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 PGC1α, ERRα specifically mediates pro-survival functions and represents a tangible therapeutic target. Implications ERRα, a druggable protein, mediates the bioenergetic effects in melanomas defined by high PGC1α expression, suggesting a rational means for therapeutic targeting of this particularly aggressive melanoma subtype.

Inhibition of ERRα Prevents Mitochondrial Pyruvate Uptake Exposing NADPH-Generating Pathways as Targetable Vulnerabilities in Breast Cancer

“…A novel complex I inhibitor, BAY87–2243, was shown to alleviate hypoxia and improve radiation response in preclinical models, however, a phase I clinical trial with this drug had to be terminated due to unexpected toxicity (Chang et al, 2015; Ellinghaus et al, 2013). As previously shown, inhibition of ERRα also reduces OCR in breast cancer cells (Luo et al, 2017; Park et al, 2016). This might reflect the fact that many of the nuclear-encoded ETC genes are direct transcriptional targets of ERRα (Chang et al, 2011; Charest-Marcotte et al, 2010; Luo et al, 2017).…”

“…As previously shown, inhibition of ERRα also reduces OCR in breast cancer cells (Luo et al, 2017; Park et al, 2016). This might reflect the fact that many of the nuclear-encoded ETC genes are direct transcriptional targets of ERRα (Chang et al, 2011; Charest-Marcotte et al, 2010; Luo et al, 2017). Regardless, considering the mechanism of action of ERRα, and the apparent safety of inhibitors of this receptor, it is likely that drugs of this class would also function as radiosensitizers.…”

Metabolic Plasticity of Melanoma Cells and Their Crosstalk With Tumor Microenvironment

“…PGC1-α, a key regulator of mitochondrial biogenesis and metabolism, is highly expressed in melanomas with OXPHOS phenotype and it is also upregulated in BRAFi/MEKi-resistant melanomas. However, the depletion of PGC1-α should be avoided in melanoma treatment because PGC1-α has a dual role in CM: it favors tumor growth and survival through the induction of oxidative metabolism and suppresses melanoma cell invasion and metastatic dissemination (229). Therefore, the depletion of PGC1-α in melanomas not only results in acute energy deficit caused by reduction of mitochondria metabolism (230), but also makes nonmetastatic melanoma cells highly invasive (231).…”

Estrogen-related receptor alpha directly binds to p53 and cooperatively controls colon cancer growth through the regulation of mitochondrial biogenesis and function

“…Based on Warburg’s prediction, cancer cells increase metabolic requirements to sustain their proliferation [ 21 ]. ERRα is emerging as a major transcription factor that regulates an extremely broad repertoire of mitochondrial and metabolic genes [ 12 , 16 , 22 – 27 ], making this druggable protein very attractive for cancer treatment [ 28 ].…”

“…The function of the ERRα and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) transcriptional axis in the metabolic reprogramming of cancer cells toward mitochondrial metabolism in breast, melanoma, ovarian, prostate, and colorectal tumors is well-known [ 12 , 28 – 32 ]. However, whether different transcriptional networks exist, whereby ERRα could interact with important transcription factors (TFs) leading to the regulation of cancer metabolism and survival, is not clear.…”