Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
PLoS One. 2012;7(8):e40690. doi: 10.1371/journal.pone.0040690. Epub 2012 Aug 17.
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.
线粒体作为氧气传感器以及 ATP 和活性氧（ROS）的产生体的重要性最近已成为癌症研究的焦点。然而，就黑色素瘤而言，关于细胞生物能学过程在多大程度上促进疾病的进展以及与之相关的问题，以及氧化磷酸化（OXPHOS）在晚期黑色素瘤中是否具有突出作用，信息很少。在这项研究中，我们证明与黑素细胞相比，转移性黑色素瘤细胞具有更高水平的 OXPHOS。此外，用药物 Elesclomol 处理转移性黑色素瘤细胞，该药物通过氧化应激诱导癌细胞凋亡，我们通过稳定同位素标记与细胞培养中的氨基酸（SILAC）记录到参与 OXPHOS 的蛋白质下调。我们还提供了证据表明，具有高水平糖酵解的黑色素瘤细胞对 Elesclomol 更具抵抗力。我们进一步表明，Elesclomol 上调低氧诱导因子 1-α（HIF-1α），并且黑色素瘤细胞长时间暴露于该药物会导致选择具有高水平糖酵解的黑色素瘤细胞。总之，我们的研究结果表明，针对 OXPHOS 的分子靶向可能对晚期黑色素瘤有效。
