Dissociation of NSC606985 induces atypical ER-stress and cell death in prostate cancer cells

  • Authors:
    • Liping Wang
    • Pengcheng Fu
    • Yuan Zhao
    • Guo Wang
    • Richard Yu
    • Xin Wang
    • Zehai Tang
    • Julianne Imperato-McGinley
    • Yuan-Shan Zhu
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  • Published online on: June 2, 2016     https://doi.org/10.3892/ijo.2016.3555
  • Pages: 529-538
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Abstract

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.
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August-2016
Volume 49 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Wang L, Fu P, Zhao Y, Wang G, Yu R, Wang X, Tang Z, Imperato-McGinley J and Zhu Y: Dissociation of NSC606985 induces atypical ER-stress and cell death in prostate cancer cells. Int J Oncol 49: 529-538, 2016
APA
Wang, L., Fu, P., Zhao, Y., Wang, G., Yu, R., Wang, X. ... Zhu, Y. (2016). Dissociation of NSC606985 induces atypical ER-stress and cell death in prostate cancer cells. International Journal of Oncology, 49, 529-538. https://doi.org/10.3892/ijo.2016.3555
MLA
Wang, L., Fu, P., Zhao, Y., Wang, G., Yu, R., Wang, X., Tang, Z., Imperato-McGinley, J., Zhu, Y."Dissociation of NSC606985 induces atypical ER-stress and cell death in prostate cancer cells". International Journal of Oncology 49.2 (2016): 529-538.
Chicago
Wang, L., Fu, P., Zhao, Y., Wang, G., Yu, R., Wang, X., Tang, Z., Imperato-McGinley, J., Zhu, Y."Dissociation of NSC606985 induces atypical ER-stress and cell death in prostate cancer cells". International Journal of Oncology 49, no. 2 (2016): 529-538. https://doi.org/10.3892/ijo.2016.3555