Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis.
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.
Nawrocki
Steffan T
ST
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, 77030, USA.
Carew
Jennifer S
JS
Pino
Maria S
MS
Highshaw
Ralph A
RA
Dunner
Kenneth
K
Huang
Peng
P
Abbruzzese
James L
JL
McConkey
David J
DJ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D002118:Calcium / Q000378:metabolism*; D002273:Carcinogens / Q000494:pharmacology; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D045304:Cytochromes c; D004347:Drug Interactions; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011719:Pyrazines / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D014410:Tumor Stem Cell Assay; D014415:Tunicamycin / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001897:Boronic Acids; D002273:Carcinogens; D061945:Caspase Inhibitors; D011719:Pyrazines; D034741:RNA, Small Interfering; D014415:Tunicamycin; D019284:Thapsigargin; D000069286:Bortezomib; D045304:Cytochromes c; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases; D002945:Cisplatin; D002118:Calcium