Cellular Inhibitor of Apoptosis Protein 1 (cIAP1) Stability Contributes to YM155 Resistance in Human Gastric Cancer Cells
Cellular Inhibitor of Apoptosis Protein 1 (cIAP1) Stability Contributes to YM155 Resistance in Human Gastric Cancer Cells
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DOI：
10.1074/jbc.m114.600874
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发表时间：
2015-04-17
影响因子：
4.8
通讯作者：
Kim, TaeWon
中科院分区：
文献类型：
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作者：
Jung, Soo-A;Park, Yong-Man;Kim, TaeWon
YM155阻断凋亡抑制剂（IAP）家族成员存活素的表达，诱导多种癌症类型中的细胞死亡，包括前列腺癌、膀胱癌、乳腺癌、白血病和非小细胞肺癌。然而，胃癌对YM 155的易感性和耐药性的机制尚未明确。在这里，我们证明了cIAP1的稳定性决定了人胃癌细胞对YM155的耐药性。用YM155处理人胃癌细胞差异诱导依赖于cIAP 1以及生存素稳定性的细胞死亡。用cIAP1表达质粒转染降低细胞对YM155的敏感性，而使用RNA干扰敲低内源性cIAP1增强对YM155的敏感性。此外，生存素和cIAP 1的双敲低显著诱导YM155抗性细胞系MKN 45中的细胞死亡。我们还表明，YM155诱导autoubiquitination和蛋白酶体依赖性降解cIAP 1。令人惊讶的是，生存素通过结合影响cIAP1的稳定性，有助于细胞对YM155的敏感性。因此，我们的研究结果表明，YM155通过降解cIAP 1使人胃癌细胞对凋亡性细胞死亡敏感，此外，胃癌细胞中的cIAP 1可以作为YM155治疗的PD标志物。
YM155, which blocks the expression of survivin, a member of the inhibitor of apoptosis (IAP) family, induces cell death in a variety of cancer types, including prostate, bladder, breast, leukemia, and non-small lung cancer. However, the mechanism underlying gastric cancer susceptibility and resistance to YM155 is yet to be specified. Here, we demonstrate that cIAP1 stability dictates resistance to YM155 in human gastric cancer cells. Treatment of human gastric cancer cells with YM155 differentially induced cell death dependent on the stability of cIAP1 as well as survivin. Transfection with cIAP1 expression plasmids decreased cell sensitivity to YM155, whereas knockdown of endogenous cIAP1 using RNA interference enhanced sensitivity to YM155. In addition, double knockdown of survivin and cIAP1 significantly induced cell death in the YM155-resistant cell line, MKN45. We also showed that YM155 induced autoubiquitination and proteasome-dependent degradation of cIAP1. Surprisingly, survivin affected the stability of cIAP1 through binding, contributing to cell sensitivity to YM155. Thus, our findings reveal that YM155 sensitizes human gastric cancer cells to apoptotic cell death by degrading cIAP1, and furthermore, cIAP1 in gastric cancer cells may act as a PD marker for YM155 treatment.