Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis

Steffan T. Nawrocki, Jennifer S. Carew, Maria S. Pino, Ralph A. Highshaw, Kenneth Dunner, Peng Huang, James L. Abbruzzese, David J. McConkey

Research output: Contribution to journalArticle

Abstract

Bortezomib (PS-341, Velcade) is a potent and selective inhibitor of the proteasome that is currently under investigation for the treatment of solid malignancies. We have shown previously that bortezomib has activity in pancreatic cancer models and that the drug induces endoplasmic reticulum (ER) stress but also suppresses the unfolded protein response (UPR). Because the UPR is an important cytoprotective mechanism, we hypothesized that bortezomib would sensitize pancreatic cancer cells to ER stress-mediated apoptosis. Here, we show that bortezomib promotes apoptosis triggered by classic ER stress inducers (tunicamycin and thapsigargin) via a c-Jun NH2-terminal kinase (JNK)-dependent mechanism. We also show that cisplatin stimulates ER stress and interacts with bortezomib to increase ER dilation, intracellular Ca2+ levels, and cell death. Importantly, combined therapy with bortezomib plus cisplatin induced JNK activation and apoptosis in orthotopic pancreatic tumors resulting in a reduction in tumor burden. Taken together, our data establish that bortezomib sensitizes pancreatic cancer cells to ER stress-induced apoptosis and show that bortezomib strongly enhances the anticancer activity of cisplatin.

Original languageEnglish (US)
Pages (from-to)11658-11666
Number of pages9
JournalCancer Research
Volume65
Issue number24
DOIs
StatePublished - Dec 15 2005
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Nawrocki, S. T., Carew, J. S., Pino, M. S., Highshaw, R. A., Dunner, K., Huang, P., Abbruzzese, J. L., & McConkey, D. J. (2005). Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis. Cancer Research, 65(24), 11658-11666. https://doi.org/10.1158/0008-5472.CAN-05-2370