Receptor-interacting protein 1 increases chemoresistance by maintaining inhibitor of apoptosis protein levels and reducing reactive oxygen species through a microRNA-146a-mediated catalase pathway [Cell Biology]

January 14th, 2014 by Wang, Q., Chen, W., Bai, L., , Padilla, M. T., Lin, A. S., Shi, S., Wang, X., Lin, Y.

Although receptor-interacting protein 1 (RIP1) is well known as a key mediator in cell survival and death signaling, whether RIP1 directly contributes to chemotherapy response in cancer has not been determined. In this report, we found that in human lung cancer cells, knockdown of RIP1 substantially increased cytotoxicity induced by frontline anticancer therapeutic cisplatin, which was associated with robust cellular reactive oxygen species (ROS) accumulationand enhanced apoptosis. Scavenging ROS dramatically protected RIP1 knockdown cells against cisplatin-induced cytotoxicity. Furthermore, we found that in RIP1 knockdown cells the expression of the hydrogen peroxide-reducing enzyme, catalase, was dramatically reduced, which was associated with increased miR-146a expression. Inhibition of miR-146a restored catalase expression, suppressed ROS induction, and protected against cytotoxicity in cisplatin-treated RIP1 knockdown cells, suggesting RIP1 maintains catalase expression to restrain ROS levels in therapy response in cancer cells. Additionally, cisplatinsignificantly triggeredproteasomal degradation of cell survival proteins,c-IAP1, c-IAP2 and XIAP in a ROS-dependent manner, and in RIP1 knockdown cells, ectopic expression of c-IAP1 and c-IAP2 attenuated cisplatin-induced cytotoxicity. Thus, our results establish a chemoresistant role for RIP1 that maintains IAP expression by release of miR-146a-mediated catalase suppression, where intervention within this pathway may be exploited for chemosensitization.
  • Posted in Journal of Biological Chemistry, Publications
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