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Michelle Barbi de Moura1, Garret Vincent, Shelley L Fayewicz
1Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
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.
Insights
Metastatic melanoma cells show increased oxidative phosphorylation (OXPHOS). Targeting OXPHOS may be effective for advanced melanoma, as resistance develops through glycolysis when treated with Elesclomol.
Area of Science:
- Mitochondrial biology
- Cancer research
- Melanoma progression
Background:
- Mitochondria are key in cancer, influencing ATP production, ROS signaling, and oxygen sensing.
- The role of cellular bioenergetics, particularly oxidative phosphorylation (OXPHOS), in melanoma progression remains unclear.
- Understanding OXPHOS in advanced melanoma is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of OXPHOS in metastatic melanoma.
- To determine the effect of Elesclomol, an oxidative stress-inducing drug, on OXPHOS in melanoma cells.
- To explore the relationship between glycolysis, OXPHOS, and resistance to Elesclomol.
Main Methods:
- Comparative analysis of OXPHOS levels in melanocytes versus metastatic melanoma cells.
- Stable Isotope Labeling with Amino acids in cell culture (SILAC) to quantify protein changes.
- Assessment of drug resistance mechanisms and hypoxia-inducible factor 1-alpha (HIF-1α) regulation.
Main Results:
- Metastatic melanoma cells exhibit significantly higher OXPHOS levels than melanocytes.
- Elesclomol treatment downregulates OXPHOS proteins and induces apoptosis via oxidative stress.
- Melanoma cells with high glycolysis show increased resistance to Elesclomol, with prolonged exposure selecting for these cells.
- Elesclomol treatment leads to upregulation of HIF-1α.
Conclusions:
- OXPHOS plays a significant role in advanced melanoma.
- Targeting OXPHOS presents a potential therapeutic strategy for advanced melanoma.
- Glycolytic adaptation confers resistance to oxidative stress-inducing therapies like Elesclomol.
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