Dissociation of NSC606985 induces atypical ER-stress and cell death in prostate cancer cells.
Castration-resistant prostate cancer (CRPC) is a major cause of prostate cancer (Pca) death. Chemotherapy is able to improve the survival of CRPC patients. We previously found that NSC606985 (NSC), a highly water-soluble camptothecin analog, induced cell death in Pca cells via interaction with topoisomerase 1 and activation of the mitochondrial apoptotic pathway. To further elucidate the role of NSC, we studied the effect of NSC on ER-stress and its association with NSC-induced cell death in Pca cells. NSC produced a time- and dose-dependent induction of GRP78, CHOP and XBP1s mRNA, and CHOP protein expression in Pca cells including DU145, indicating an activation of ER-stress. However, unlike conventional ER-stress in which GRP78 protein is increased, NSC produced a time- and dose-dependent U-shape change in GRP78 protein in DU145 cells. The NSC-induced decrease in GRP78 protein was blocked by protease inhibitors, N-acetyl-L-leucyl-L-leucylnorleucinal (ALLN), a lysosomal protease inhibitor, and epoxomicin (EPO), a ubiquitin-protease inhibitor. ALLN, but not EPO, also partially inhibited NSC-induced cell death. However, both 4-PBA and TUDCA, two chemical chaperons that effectively reduced tunicamycin-induced ER-stress, failed to attenuate NSC-induced GRP78, CHOP and XBP1s mRNA expression and cell death. Moreover, knockdown of NSC induction of CHOP expression using a specific siRNA had no effect on NSC-induced cytochrome c release and NSC-induced cell death. These results suggest that NSC produced an atypical ER-stress that is dissociated from NSC-induced activation of the mitochondrial apoptotic pathway and NSC-induced cell death in DU145 prostate cancer cells.
Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
Liping
L
Wang
Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
Pengcheng
P
Fu
Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
Yuan
Y
Zhao
Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
Guo
G
Wang
Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
Richard
R
Yu
Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
Xin
X
Wang
Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
Zehai
Z
Tang
Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
Julianne
J
Imperato-McGinley
Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
Yuan-Shan
YS
Zhu
D017209:Apoptosis / Q000187:drug effects; D002082:Butylamines / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology
C121358:4-phenylbutylamine; D002082:Butylamines; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C514334:NSC606985; D011480:Protease Inhibitors; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D002166:Camptothecin