Insulin-like growth factor 1 mediates 5-fluorouracil chemoresistance in esophageal carcinoma cells through increasing survivin stability
Insulin-like growth factor 1 mediates 5-fluorouracil chemoresistance in esophageal carcinoma cells through increasing survivin stability
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DOI：
10.1007/s10495-010-0555-z
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发表时间：
2011-02-01
期刊：
影响因子：
7.2
通讯作者：
Wong, Fen-Hwa
中科院分区：
文献类型：
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作者：
Juan, Hsien-Chia;Tsai, Hsin-Ting;Wong, Fen-Hwa
胰岛素样生长因子1（IGF-1）抑制5-氟尿嘧啶（5-Fu）诱导的食管癌细胞凋亡，但IGF-1诱导5-Fu耐药的机制尚不清楚。在人食管癌细胞系CE 48 T/VGH中，我们发现IGF-1在转录后水平上调survivin的表达，这种上调是由PI 3-K/Akt和酪蛋白激酶2信号通路介导的。然后，我们研究是否IGF-1诱导的5-Fu化疗耐药性介导的生存素的上调。Survivin的异位表达抑制5-Fu诱导的细胞凋亡;此外，Survivin表达的消除使细胞对5-Fu治疗敏感，并阻止IGF-1在食管癌细胞系中的抗凋亡功能。我们还发现，异位表达的生存素或治疗与IGF-1抑制释放Smac/DIABLO和半胱天冬酶激活后，5-Fu治疗。我们的研究结果强烈表明，IGF-1抑制5-Fu诱导的细胞凋亡，通过增加生存素水平，阻止Smac/DIABLO释放和阻断半胱天冬酶的激活。因此，IGF-1和Survivin的表达上调可能是食管癌患者5-Fu耐药的原因之一，这些因素可能是食管癌5-Fu耐药的有价值的预测指标。
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.