Mitochondrial Respiration - An Important Therapeutic Target in Melanoma

Abstract

The importance of mitochondria as oxygen sensors as well as producers of ATP and reactive oxygen species (ROS) has recently become a focal point of cancer research. However, in the case of melanoma, little information is available to what extent cellular bioenergetics processes contribute to the progression of the disease and related to it, whether oxidative phosphorylation (OXPHOS) has a prominent role in advanced melanoma. In this study we demonstrate that compared to melanocytes, metastatic melanoma cells have elevated levels of OXPHOS. Furthermore, treating metastatic melanoma cells with the drug, Elesclomol, which induces cancer cell apoptosis through oxidative stress, we document by way of stable isotope labeling with amino acids in cell culture (SILAC) that proteins participating in OXPHOS are downregulated. We also provide evidence that melanoma cells with high levels of glycolysis are more resistant to Elesclomol. We further show that Elesclomol upregulates hypoxia inducible factor 1-α (HIF-1α), and that prolonged exposure of melanoma cells to this drug leads to selection of melanoma cells with high levels of glycolysis. Taken together, our findings suggest that molecular targeting of OXPHOS may have efficacy for advanced melanoma.

Mitochondrial oxidative stress as a novel therapeutic target to overcome intrinsic drug resistance in melanoma cell subpopulations

“…Corresponding to our earlier observations (4) and the literature (10,12), we have confirmed that mitochondrial H 2 O 2 levels are significantly elevated in melanoma cells upon exogenous overexpression of JARID1B (Figure S1a) and that elesclomol induces oxidative stress and cell number reduction irrespective of melanoma cell genotypes (Figures S1b, c and S2). The three-dimensional growth as spheroids and the invasion into collagen were also decreased (Figure S3).…”

“…Elesclomol–copper complexes can induce oxidative stress and cell death by disruption of the mitochondrial respiration chain or by indirect non-mitochondrial formation of reactive oxygen species (ROS) (7–10). Alternatively, (unbound) copper is required for melanoma cell signalling and tumorigenesis (11).…”

Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis

“…Suppression of glycolysis concomitant with enhanced fatty acid oxidation and increased steady-state levels of several TCA cycle intermediates, including oxaloacetate, strongly suggest that TRAP1-deficient cells use one or more anaplerotic mechanisms to sustain their mitochondrial metabolism. Intriguingly, a nearly identical metabolic phenotype has been described for castrate-resistant prostate cancer (45), and a recent study suggests that oxidative phosphorylation may play a prominent role in advanced melanoma (46). Although evaluation of TRAP1-specific inhibitors warrants further exploration as a novel approach to cancer therapy, our findings would suggest that TRAP1 inhibition alone is unlikely to be a viable treatment strategy for cancers that use oxidative phosphorylation.…”

“…Recent studies have shown that utilization of alternative carbon sources affects tumor evolution, and the role of oxidative phosphorylation in cancer metabolism has not been fully appreciated (46,(51)(52)(53)(54). Furthermore, the ability of normal as well as cancer cells to rapidly adjust their metabolic behavior in response to environmental conditions and cellular requirements is essential to survival and the metabolic requirements of proliferating and nonproliferating cells are distinct, as are the metabolic demands underlying tumor initiation, metastasis, and growth at distant sites (55,56).…”

Oxidative Stress and Mitochondrial Dysfunction across Broad-Ranging Pathologies: Toward Mitochondria-Targeted Clinical Strategies

“…Mitochondria from metastatic melanoma cells displayed increased expression of OXPHOS activities versus nonneoplastic melanocytes [232]. …”