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- W2736780977 abstract "A65 The second mitochondria-derived activator of caspase (Smac) promotes the activation of caspases by blocking inhibitor of apoptosis (IAP) proteins, thereby enhancing apoptosis. Two head and neck tumor cell lines, UM-SCC-5 and -10B, were selected for cisplatin resistance in vitro by exposure to increasing concentrations of cisplatin. These cisplatin-resistant cell line derivatives, UM-SCC-5PT and -10BPT, exhibited reduced Smac mRNA and protein expression relative to the cisplatin-sensitive UM-SCC-5 and -10B. Using a lentiviral system to stably transduce UM-SCC-10B with one of two different Smac shRNAs or a scrambled control shRNA, we analyzed the role of SMAC in escape from cisplatin-induced apoptosis. Western blot analysis confirmed greater than 80% knockdown of Smac expression in both Smac shRNA transduced cell lines relative to nontransduced and scrambled shRNA controls. Additionally, cell lines expressing Smac shRNA exhibited 17-25% less apoptosis by TUNEL assay in response to 10µM cisplatin than nontransduced and scrambled shRNA controls cells. To test the mechanism leading to loss of Smac expression, UM-SCC-5PT and -10BPT cells were assayed for Smac protein expression 96 hours after a 48-hour treatment with 15µM or 30µM 5-Azacytidine, an inhibitor of DNA methyltransferase. In both UM-SCC-5PT and -10BPT, Smac protein expression was restored following treatment with 5-Azacytidine. Furthermore, caspase-3 activity increased 3 to 4-fold in UM-SCC-5PT and -10BPT following 48-hour exposure to 10µM cisplatin in cells pretreated with 5-Azacytidine relative to untreated controls. Therefore, our results are the first to indicate that restoring Smac expression with methyltransferase inhibitors such as 5-Azacytidine will sensitize cisplatin-resistant squamous carcinoma cells to cisplatin-induced apoptosis. This research was supported by the National Cancer Institute Head and Neck SPORE grant P50 CA97248, National Institute of Dental and Craniofacial Research DE13346, National Cancer Institute CA83087, National Institute of General Medical Sciences GM07767, National Institute on Deafness and Other Communication Disorders T32 DC00011 and P30 DC05188, and Cancer Center Support grant 5 P30 CA46592." @default.
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- W2736780977 date "2007-10-01" @default.
- W2736780977 modified "2023-09-23" @default.
- W2736780977 title "Methylation contributes to decreased Smac expression and resistance to cisplatin-induced apoptosis in head and neck squamous cell carcinomas" @default.
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