Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis.
Journal Article (Journal Article)
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 NH(2)-terminal kinase (JNK)-dependent mechanism. We also show that cisplatin stimulates ER stress and interacts with bortezomib to increase ER dilation, intracellular Ca(2+) 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.
Full Text
Duke Authors
Cited Authors
- Nawrocki, ST; Carew, JS; Pino, MS; Highshaw, RA; Dunner, K; Huang, P; Abbruzzese, JL; McConkey, DJ
Published Date
- December 15, 2005
Published In
Volume / Issue
- 65 / 24
Start / End Page
- 11658 - 11666
PubMed ID
- 16357177
International Standard Serial Number (ISSN)
- 0008-5472
Digital Object Identifier (DOI)
- 10.1158/0008-5472.CAN-05-2370
Language
- eng
Conference Location
- United States