Mitochondrial respiration--an important therapeutic target in melanoma.
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.
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Michelle
M
Barbi de Moura
Garret
G
Vincent
Shelley L
SL
Fayewicz
Nicholas W
NW
Bateman
Brian L
BL
Hood
Mai
M
Sun
Joseph
J
Suhan
Stefan
S
Duensing
Yan
Y
Yin
Cindy
C
Sander
John M
JM
Kirkwood
Dorothea
D
Becker
Thomas P
TP
Conrads
Bennett
B
Van Houten
Stergios J
SJ
Moschos
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D058990:Molecular Targeted Therapy / Q000379:methods*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D006834:Hydrazines; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C512195:elesclomol