Enhancement of Apo2L/TRAIL-mediated cytotoxicity in esophageal cancer cells by cisplatin

• Published in: Molecular cancer therapeutics Vol. 5; no. 12; pp. 2977 - 2990
• Main Authors: Tsai, Wilson S, Yeow, Wen-Shuz, Chua, Alex, Reddy, Rishindra M, Nguyen, Duc M, Schrump, David S, Nguyen, Dao M
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.12.2006
• Subjects: Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apo2L/TRAIL; Apoptosis - drug effects; caspase; Caspases - metabolism; Cell Line, Tumor; cisplatin; Cisplatin - administration & dosage; Cisplatin - pharmacology; Death Domain Receptor Signaling Adaptor Proteins - biosynthesis; Drug Screening Assays, Antitumor; Drug Synergism; Enzyme Activation; esophageal cancer; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Humans; Isoenzymes - metabolism; mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; TNF-Related Apoptosis-Inducing Ligand - administration & dosage; TNF-Related Apoptosis-Inducing Ligand - pharmacology
• DOI: 10.1158/1535-7163.MCT-05-0514
• ISSN: 1535-7163

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]