Bortezomib (Velcade) induces p27Kip1 expression through S-phase kinase protein 2 degradation in colorectal cancer.
Bortezomib (Velcade) induces p27Kip1 expression through S-phase kinase protein 2 degradation in colorectal cancer.
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DOI：
10.1158/0008-5472.can-07-6109
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发表时间：
2008-05
期刊：
影响因子：
11.2
通讯作者：
S. Uddin;Maqbool Ahmed;P. Bavi;raafat El-Sayed;N. Al‐Sanea;Alaa S. Abduljabbar;L. Ashari;S. Alhomoud;F. Al-Dayel;A. Hussain;K. Al-Kuraya
中科院分区：
文献类型：
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作者：
S. Uddin;Maqbool Ahmed;P. Bavi;raafat El-Sayed;N. Al‐Sanea;Alaa S. Abduljabbar;L. Ashari;S. Alhomoud;F. Al-Dayel;A. Hussain;K. Al-Kuraya
S期激酶蛋白2（SKP 2）是一种F-box蛋白，通过泛素介导的降解作用靶向细胞周期调节因子，包括周期依赖性激酶抑制剂p27 Kip 1。SKP 2在多种癌症中经常过表达。我们使用一组细胞系、临床样本和裸鼠模型研究了SKP 2及其泛素-蛋白酶体通路在结直肠癌中的作用。对448个样本的大型组织芯片进行免疫组化分析，发现SKP 2表达与p27 Kip 1蛋白水平呈负相关。高SKP 2水平和低p27 Kip 1水平的结直肠癌（CRC）亚群显示总生存率降低（P = 0.0057）。用硼替佐米或SKP 2的小干扰RNA表达处理CRC细胞系导致SKP 2下调和p27 Kip 1积累。此外，用硼替佐米处理CRC细胞通过涉及线粒体途径和半胱天冬酶的活化引起细胞凋亡。此外，用硼替佐米处理CRC细胞下调了XIAP、cIAP 1和生存素的表达。最后，用硼替佐米处理CRC细胞系异种移植物通过SKP 2的下调和p27 Kip 1的积累导致NUDE小鼠中肿瘤的生长抑制。总之，我们的研究结果表明，SKP 2和泛素-蛋白酶体通路可能是治疗CRC的潜在靶点。
S-phase kinase protein 2 (SKP2), an F-box protein, targets cell cycle regulators including cycle-dependent kinase inhibitor p27Kip1 via ubiquitin-mediated degradation. SKP2 is frequently overexpressed in a variety of cancers. We investigated the role of SKP2 and its ubiquitin-proteasome pathway in colorectal carcinoma using a panel of cell lines, clinical samples, and the NUDE mouse model. Using immunohistochemical analysis on a large tissue microarray of 448 samples, an inverse association of SKP2 expression with p27Kip1 protein levels was seen. A colorectal cancer (CRC) subset with high level of SKP2 and low level of p27Kip1 showed a decreased overall survival (P = 0.0057). Treatment of CRC cell lines with bortezomib or expression of small interfering RNA of SKP2 causes down-regulation of SKP2 and accumulation of p27Kip1. Furthermore, treatment of CRC cells with bortezomib causes apoptosis by involving the mitochondrial pathway and activation of caspases. In addition, treatment of CRC cells with bortezomib down-regulated the expression of XIAP, cIAP1, and survivin. Finally, treatment of CRC cell line xenografts with bortezomib resulted in growth inhibition of tumors in NUDE mice via down-regulation of SKP2 and accumulation of p27Kip1. Altogether, our results suggest that SKP2 and the ubiquitin-proteasome pathway may be potential targets for therapeutic intervention for treatment of CRC.