Mitochondrial respiration - an important therapeutic target in melanoma

Michelle Barbi de Moura, Garret Vincent, Shelley L. Fayewicz, Nicholas W. Bateman, Brian L. Hood, Mai Sun, Joseph Suhan, Stefan Duensing, Yan Yin, Cindy Sander, John M. Kirkwood, Dorothea Becker, Thomas P. Conrads, Bennett van Houten, Stergios J. Moschos

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

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.

Original languageEnglish
Article numbere40690
JournalPLoS ONE
Volume7
Issue number8
DOIs
StatePublished - 17 Aug 2012
Externally publishedYes

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