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.
Highlights
Despite the recent US Food and Drug Administration (FDA) approval of novel therapies for advanced melanoma, the prognosis for locally advanced and stage IV melanoma remains poor because of emerging resistance to molecular therapies, and the relatively low number of patients with metastatic melanoma who benefit from immunotherapies [1,2]
It has been previously reported that Elesclomol treatment increases reactive oxygen species (ROS) in melanoma and other cancer cells, an observation we confirmed in WM1158 metastatic melanoma cells that were treated for 1 hr with increasing doses of Elesclomol (20, 100, or 500 nM, data not shown)
This study demonstrated that mitochondrial function exerts important functions relevant to melanoma cell survival and death, and that the drug Elesclomol targets a pertinent cellular function in melanoma
Summary
Despite the recent US Food and Drug Administration (FDA) approval of novel therapies for advanced melanoma, the prognosis for locally advanced and stage IV melanoma remains poor because of emerging resistance to molecular therapies, and the relatively low number of patients with metastatic melanoma who benefit from immunotherapies [1,2]. We present novel and important data, which show that cellular bioenergetics and, in particular, mitochondrial functions play an important role in this disease. To date, little is known regarding the role of mitochondrial functions, such as redox regulation and OXPHOS, in melanoma progression and survival. A previous study, which investigated redox regulation in melanoma progression focused on the physicochemical properties of melanin as an anti-oxidant or a pro-oxidant [6]. These mitochondrial functions are linked because oxygen levels affect the dependence of cells on OXPHOS for energy production and the production of reactive oxygen species (ROS). The other important question that has not yet been systematically addressed is whether melanoma cells rely more on OXPHOS or glycolysis [7,8]
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