PINCH-1 regulates the ERK-Bim pathway and contributes to apoptosis resistance in cancer cells
PINCH-1 regulates the ERK-Bim pathway and contributes to apoptosis resistance in cancer cells
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DOI：
10.1074/jbc.m707307200
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发表时间：
2008-02-01
影响因子：
4.8
通讯作者：
Wu, Chuanyue
中科院分区：
文献类型：
--
作者：
Chen, Ka;Tu, Yizeng;Wu, Chuanyue
对细胞凋亡的抗性是癌细胞的标志。我们在这里报告，PINCH-1，细胞-细胞外基质粘附的细胞质组分，是保护多种类型的癌细胞免于凋亡所必需的。此外，使用HT-1080纤维肉瘤细胞作为模型系统，我们已经研究了PINCH-1通过其有助于抗凋亡的信号通路。PINCH-1的缺失显著增加Bim的水平，并促进Bim易位至线粒体，导致内源性凋亡途径的激活。Bim的缺失完全阻断了PINCH-1的缺失所诱导的细胞凋亡。因此，PINCH-1通过抑制Bim参与了细胞凋亡抵抗。从机制上讲，PINCH-1不仅在转录上而且在转录后抑制Bim。PINCH-1促进Src家族激酶和ERK 1/2的活化磷酸化。与此相一致，ERK 1/2介导的Ser 69磷酸化Bim，一个关键的信号，营业额的Bim，被抑制的PINCH-1的去除。我们的研究结果证明了多种类型的抗凋亡癌细胞对PINCH-1的强烈依赖性，并为癌细胞保护免于凋亡的分子机制提供了新的见解。
Resistance to apoptosis is a hallmark of cancer cells. We report here that PINCH-1, a cytoplasmic component of cell-extracellular matrix adhesions, is required for protection of multiple types of cancer cells from apoptosis. Furthermore, using HT-1080 fibrosarcoma cells as a model system, we have investigated the signaling pathway through which PINCH-1 contributes to apoptosis resistance. Loss of PINCH-1 markedly increases the level of Bim and promotes Bim translocation to mitochondria, resulting in activation of the intrinsic apoptosis pathway. Depletion of Bim completely blocked apoptosis induced by the loss of PINCH-1.Thus, PINCH-1 contributes to apoptosis resistance through suppression of Bim. Mechanistically, PINCH-1 suppresses Bim not only transcriptionally but also post-transcriptionally. PINCH-1 promotes activating phosphorylation of Src family kinase and ERK1/2. Consistent with this, ERK1/2-mediated Ser69 phosphorylation of Bim, a key signal for turnover of Bim, is suppressed by the removal of PINCH-1. Our results demonstrate a strong dependence of multiple types of apoptosis-resistant cancer cells on PINCH-1 and provide new insights into the molecular mechanism by which cancer cells are protected from apoptosis.