VCP inhibitors induce endoplasmic reticulum stress, cause cell cycle arrest, trigger caspase-mediated cell death and synergistically kill ovarian cancer cells in combination with Salubrinal.

ABSTRACT: Valosin-containing protein (VCP) or p97, a member of AAA-ATPase protein family, has been associated with various cellular functions including endoplasmic reticulum-associated degradation (ERAD), Golgi membrane reassembly, autophagy, DNA repair, and cell division. Recent studies identified VCP and ubiquitin proteasome system (UPS) as synthetic lethal targets in ovarian cancer. Here, we describe the preclinical activity of VCP inhibitors in ovarian cancer. Results from our studies suggest that quinazoline-based VCP inhibitors initiate G1 cell cycle arrest, attenuate cap-dependent translation and induce programmed cell death via the intrinsic and the extrinsic modes of apoptosis. Mechanistic studies point to the unresolved unfolded protein response (UPR) as a mechanism by which VCP inhibitors

SUBMITTER: Bastola P 

PROVIDER: S-EPMC5423134 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature