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- Title
Bortezomib-induced apoptosis in cultured pancreatic cancer cells is associated with ceramide production.
- Authors
Gong, Lei; Yang, Bo; Xu, Ming; Cheng, Bo; Tang, Xuejun; Zheng, Ping; Jing, Yan; Wu, Gao-jue
- Abstract
Purpose: The proteasome inhibitor bortezomib (PS-341) has displayed significant efficiency against pancreatic cancer cells. However, the underlying mechanisms are not fully understood. Here, we tested if ceramide production was involved in the bortezomib's effect. Methods: Two transformed pancreatic cancer cell lines (PANC-1 and Mia) and the primary pancreatic cancer cells were used. Cell death was analyzed by MTT viability assay and trypan blue staining. Cell apoptosis was analyzed by Histone DNA-ELISA assay and Annexin V FACS. Western blots were used to test signal protein changes. The cellular ceramide level after bortezomib treatment was also determined. Results: In cultured pancreatic cancer cells, bortezomib increased cellular ceramide production to promote cell apoptosis. The ceramide de novo synthase inhibitor fumonisin B1 (F-B1) suppressed bortezomib-induced ceramide production and apoptosis, while exogenously added C6-ceramide facilitated bortezomib-induced pancreatic cancer cell death. Meanwhile, 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), the inhibitor of glucosylceramide synthetase as well as the sphingosine kinase 1 inhibitors (SKI-II and SKI-IV), facilitated bortezomib-induced ceramide production and subsequent cell apoptosis. Further, bortezomib-induced pro-apoptotic c-Jun N-terminal kinase (JNK) activation was also associated with ceramide production. JNK activation by bortezomib was suppressed by F-B1, but was enhanced by SKI-II and PDMP in pancreatic cancer cells. Finally, C6-ceramide, SKI-II, and PDMP dramatically enhanced bortezomib-induced cytotoxicity in primary cultured pancreatic cancer cells. Conclusions: We found that bortezomib-induced apoptosis was associated with ceramide production in primary and transformed pancreatic cancer cells.
- Subjects
PANCREATIC cancer treatment; BORTEZOMIB; APOPTOSIS; CANCER cells; CERAMIDES; PROTEASOME inhibitors
- Publication
Cancer Chemotherapy & Pharmacology, 2014, Vol 73, Issue 1, p69
- ISSN
0344-5704
- Publication type
Academic Journal
- DOI
10.1007/s00280-013-2318-3