ERdj5 sensitizes neuroblastoma cells to endoplasmic reticulum stress-induced apoptosis.
J Biol Chem. 2009 Jan 4;
Authors: Thomas CG, Spyrou G
Downregulation of the unfolded protein response (UPR) can be therapeutically valuable in cancer treatment and Endoplasmic Reticulum (ER)-resident chaperone proteins may thus be targets for developing novel chemotherapeutic strategies. ERdj5 is a novel ER chaperone that regulates the ER-associated degradation of misfolded proteins through its associations with EDEM and the ER stress sensor BiP. To investigate whether ERdj5 can regulate ER stress signaling pathways, we exposed neuroblastoma cells overexpressing ERdj5 to ER stress inducers. ERdj5 promoted apoptosis in tunicamycin, thapsigargin and bortezomib-treated cells. To provide further evidence that ERdj5 induces ER stress-regulated apoptosis, we targeted Bcl-2 to ER of ERdj5-overexpressing cells. Targeting the Bcl-2 to ER prevented the apoptosis induced by ER stress inducers but not by non-ER stress apoptotic stimuli suggesting induction of ER stress-regulated apoptosis by ERdj5. ERdj5 enhanced apoptosis by abolishing the ER stress-induced phosphorylation of translation initiation factor eIF2a and the subsequent translational repression. ERdj5 was found to inhibit the eIF2a phosphorylation under ER stress through inactivating the endoplasmic reticulum kinase PERK. The compromised integrated stress response (ISR) observed in ERdj5-overexpressing ER stressed cells due to repressed eIF2a phosphorylation correlated with impaired neuroblastoma cell resistance under ER stress. These results demonstrate that ERdj5 decreases neuroblastoma cell survival by downregulating the UPR, raising the possibility for this protein to be a target for antitumor approaches.
PMID: 19122239 [PubMed - as supplied by publisher]