Enhancement of Apo2L/TRAIL-mediated cytotoxicity in esophageal cancer cells by cisplatin
Although expressing adequate levels of functional tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptors DR4/DR5, significant proportion of cancer cells exhibit resistance to the cytotoxic effect of this ligand. Exposure of Apo2L/TRAIL-refractory cancer cells to cytotoxic chemothe...
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Published in | Molecular cancer therapeutics Vol. 5; no. 12; pp. 2977 - 2990 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Association for Cancer Research
01.12.2006
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Subjects | |
Online Access | Get full text |
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Summary: | Although expressing adequate levels of functional tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptors
DR4/DR5, significant proportion of cancer cells exhibit resistance to the cytotoxic effect of this ligand. Exposure of Apo2L/TRAIL-refractory
cancer cells to cytotoxic chemotherapeutic agents enhances their sensitivity to Apo2L/TRAIL cytotoxicity. This study aims
to elucidate the molecular mechanism responsible for the cisplatin-mediated enhancement of Apo2L/TRAIL sensitivity in cultured
esophageal cancer cells. Exposure of cancer cells to sublethal concentrations of cisplatin resulted in profound potentiation
of their susceptibility to Apo2L/TRAIL cytotoxicity as indicated by 2- to >20-fold reduction in Apo2L/TRAIL IC 50 values. Significant activation of caspase-8, caspase-9, and caspase-3 was observed only in cells treated with cisplatin/Apo2L/TRAIL
combination and not in those exposed to either agent alone. More importantly, activation of these key caspases was significantly
abrogated by overexpression of Bcl2 or by the selective caspase-9 inhibitor. This observation strongly suggested that caspase-8
activation in cells treated with the cisplatin/Apo2L/TRAIL combination was secondary to the mitochondria-mediated amplification
feedback loop and activation of the executioner caspase-3 was dependent on the recruitment of the intrinsic pathway characteristic
of the type II cell. Profound combination-mediated cytotoxicity and induction of apoptosis was completely suppressed either
by Bcl2 overexpression or by inhibition of caspase-9 activity, which conclusively pointed to the essential role of the mitochondria-dependent
death signaling cascade in this process. Cisplatin sensitizes esophageal cancer cells to Apo2L/TRAIL cytotoxicity by potentiation
of the mitochondria-dependent death signaling pathway that leads to amplification of caspase activation, particularly caspase-8,
by the feedback loop to efficiently induce apoptosis. [Mol Cancer Ther 2006;5(12):2977–90] |
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ISSN: | 1535-7163 1538-8514 |
DOI: | 10.1158/1535-7163.MCT-05-0514 |