Knockdown of CEMIP suppresses proliferation and induces apoptosis in colorectal cancer cells: downregulation of GRP78 and attenuation of unfolded protein response.

Abstract

It has been suggested that cell migration inducing hyaluronan binding protein (CEMIP) contributes to the carcinogenesis of colorectal cancer (CRC). Cancer cells can adapt to endoplasmic reticulum (ER) stress by initiating an unfolded protein response (UPR). This study aimed to investigate whether CEMIP affects the UPR of CRC cells, with a focus on 78 kDa glucose-regulated protein (GRP78, a major ER chaperone). We found that knockdown of CEMIP inhibited cell proliferation and induced a G1 arrest in SW480 CRC cells. The levels of cyclin D1 and cyclin E1 and phospho-retinoblastoma, which are known to promote the cell cycle progression from G0 or G1 into S phase, were decreased in CEMIP-silenced cells. CEMIP shRNA induced apoptosis and inhibited GRP78 expression in SW480 and Colo205 cells. The basal UPR of cancer cells was attenuated by CEMIP shRNA, as evidenced by the decreased expression of UPR sensors, protein kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). Furthermore, CEMIP silencing sensitized CRC cells to thapsigargin-induced apoptosis. Our study demonstrates that the in-vitro anti-proliferative and pro-apoptotic effects in CRC cells that were induced by silencing CEMIP may be associated with GRP78 repression and UPR attenuation.