2-deoxyglucose sensitizes melanoma cells to TRAIL-induced apoptosis which is reduced by mannose.
While melanoma cell lines use aerobic glycolysis, addition of a competitive inhibitor such as 2-deoxyglucose (2DG) by itself achieved only modest killing. To overcome high levels of pro-survival proteins in melanoma cells, 2DG or glucose deprivation (GD) was combined with tumor necrosis factor-related apoptosis inducing-ligand (TRAIL). TRAIL treatment by itself also only induced modest killing, but combining TRAIL with 2DG or GD triggered a synergistic pro-apoptotic response in melanoma lines but not melanocytes. In melanoma cells, there was cleavage of caspases 3, 8 and Bid. Killing by combination treatments was completely blocked by a pan-caspase inhibitor, z-VAD. Mechanistically, 2DG and GD enhanced surface levels for both death receptors (DR4 and DR5); which was accompanied by reductions in levels of Mcl-1, Bcl-2 and survivin. Mannose pre-treatment reduced enhanced killing by combination treatments, accompanied by reduced DR5 levels. These results indicate melanoma cells in which there is altered glucose-related metabolomics can be exploited by interfering with glucose metabolism in combination with TRAIL; thereby overcoming the notorious death resistance of melanoma. Thus, a new therapeutic window is open for future clinical trials using agents targeting the glucose-related metabolome, in combination with agents triggering death receptors in patients with melanoma.
Qin
J-Z
JZ
Department of Pathology, Loyola University Medical Center, Maywood, IL 60153-5385, United States.
Xin
H
H
Nickoloff
B J
BJ
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005947:Glucose / Q000172:deficiency / Q000494:pharmacology; D006801:Humans; D008358:Mannose / Q000494:pharmacology*; D008545:Melanoma / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
D053221:TNF-Related Apoptosis-Inducing Ligand; D003847:Deoxyglucose; D005947:Glucose; D008358:Mannose