Insulin-like Growth Factor 1 Mediates 5-fluorouracil Chemoresistance in Esophageal Carcinoma Cells Through Increasing Survivin Stability

Insulin-like growth factor 1 (IGF-1) inhibits 5-fluorouracil (5-Fu)-induced apoptosis in esophageal carcinoma cells; however, the mechanisms for IGF-1-induced 5-Fu chemoresistance remain unknown. In the human esophageal carcinoma cell line, CE48T/VGH, we show that IGF-1 up-regulated survivin expression at the post-transcriptional level and this up-regulation is mediated by both the PI3-K/Akt and casein kinase 2 signaling pathways. We then examine whether IGF-1-induced 5-Fu chemoresistance is mediated through up-regulation of survivin. Ectopic expression of survivin inhibits 5-Fu-induced apoptosis; furthermore, the abolition of survivin expression sensitizes cells to 5-Fu treatment and prevents the anti-apoptotic function of IGF-1 in esophageal carcinoma cell lines. We also found that ectopic expression of survivin or treatment with IGF-1 inhibits the release of Smac/DIABLO and caspases activation after 5-Fu treatment. Our results strongly suggest that IGF-1 inhibits 5-Fu induced apoptosis through increasing survivin levels, which prevents Smac/DIABLO release and blocks the activation of caspases. Therefore, up-regulation of IGF-1 and survivin would seem to be responsible for 5-Fu chemoresistance in esophageal cancer patients and these factors may be the valuable predictors of 5-Fu chemoresistance in esophageal carcinoma.