Bortezomib(Velcade) induces p27kip1 associated cell cycle arrest and apoptosis through down-regulation of SKP2 ubiquitin ligase pathway in colorectal carcinoma

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SKP2, an F-box protein targets cell cycle regulators including cycle-dependent kinase inhibitor p27Kip1 via ubiquitin-mediated degradation. SKP2 is frequently overexpressed in 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 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. 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 siRNA of SKP2 causes downregulation of SKP2 and accumulation of p27Kip1. Furthermore treatment of CRC cells with Bortezomib causes apoptosis via involving mitochondrial pathway and activation of caspases. In addition, treatment of CRC cells with Bortezomib downregulated 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 downregulation of SKP2 and accumulation of p27Kip1. Altogether, our results suggest that SKP2 and ubiquitin-proteasome pathway may be a potential target for therapeutic intervention for treatment of CRC.