The roles of Survivin and Aurora-A in IGF-1 mediated chemoresistance in esophageal carcinoma cells

• Main Authors: Hsien-Chia Juan, 阮絃嘉
• Other Authors: Fen-Hwa Wong
• Format: Others
• Language: en_US
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/36857379818329784779

博士 === 國立陽明大學 === 公共衛生研究所 === 99 === Insulin-like growth factor-1 (IGF-1) is a potent mitogen, which not only participates in cancer development but also plays a powerful role in cell survival. IGF-1 inhibits 5-fluorouracil (5-Fu)-induced apoptosis in human esophageal carcinoma cells; however, the molecule mechanisms that are involved in the antiapoptotic activity of IGF-1 are not well studied. Survivin, one member of the inhibitor of apoptosis family, has been reported to inhibit apoptosis, regulate cell cycle progression and promote metastasis. In this study, we showed that IGF-1 up-regulates survivin expression at post-transcriptional level through PI3-K/Akt and casein kinase 2 signaling pathways. In parallel, IGF-1 inhibits 5-Fu-induced apoptosis by up-regulation of survivin in human esophageal carcinoma cells. We also found that ectopic expression of survivin or treatment with IGF-1 inhibits the release of Smac/DIABLO and caspase 3 activation after 5-Fu treatment. We furthermore found that Aurora-A, a serine-threonine protein kinase, can be activated by IGF-1 treatment and phosphorylates survivin on Thr21 and Ser81 in vitro. Phosphorylation on Thr21 increases the protein stability and maintains the antiapoptotic function of survivin. In parallel, Aurora-A can inhibit 5-Fu-induced apoptosis through up-regulation of survivin. Altogether, we find survivin is an important mediator in IGF-1-mediated 5-Fu chemoresistance in esophageal carcinoma cells and Aurora-A can inhibit 5-Fu-induced apoptosis through up-regulation of survivin in this study. Thus, up-regulation of IGF-1, survivin and Aurora-A would seem to be responsible for 5-Fu chemoresistance in esophageal carcinoma patients and these factors may be the valuable predictors of 5-Fu chemoresistance in esophageal carcinoma patients.