Implication of oxygen-regulated protein 150 (ORP150) in apoptosis induced by proteasome inhibitors in human thyroid cancer cells.

Gao, Yan-Yan; Liu, Bao-Qin; Du, Zhen-Xian; Zhang, Hai-Yan; Niu, Xiao-Fang; Wang, Hua-Qin

Context: The inhibition of the 26S proteasome may lead to endoplasmic reticulum stress, which has been shown to be implicated in the antitumoral effects of proteasome inhibitors. Oxygen-regulated protein 150 (ORP150) is an inducible endoplasmic reticulum chaperone that is up-regulated after numerous cellular insults and has a cytoprotective role for the maintenance of cellular viability.Objective: The purpose of this study was to determine the involvement of ORP150 in cytotoxicity of thyroid cancer cells mediated by proteasome inhibition.Design: The effects of proteasome inhibition on the expression of ORP150 were analyzed using real-time RT-PCR and Western blot. To ascertain the effect of ORP150, cells were transfected with ORP150 plasmid or small interfering RNA (siRNA) against ORP150, apoptotic cells, and induction of CCAAT/enhancer-binding protein homologous transcription factor (CHOP) mediated by proteasome inhibition were investigated.Results: ORP150 was induced in thyroid cancer cells after proteasome inhibition. Suppression of activating transcription factor 4 expression by siRNA inhibited the up-regulation of ORP150 mediated by proteasome inhibitors. siRNA for ORP150 stimulated MG132-mediated apoptosis and induction of CHOP, a transcription factor with apoptosis-inducing activity. In contrast, ORP150-overexpressing cells demonstrated less susceptibility to MG132-induced apoptosis and displayed less up-regulation of CHOP. In addition, the sensitizing effect of small interfering ORP150 on apoptosis was suppressed by siRNA for CHOP.Conclusions: These results suggest that up-regulation of ORP150 in thyroid cancer cells inhibits MG132-induced apoptosis via suppression of CHOP induction, thereby decreasing the potential antitumor activity of MG132.

Journal of Clinical Endocrinology & Metabolism, 2010, Vol 95, Issue 11, pE319

0021-972X

Academic Journal

10.1210/jc.2010-1043