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Cancer Chemother Pharmacol. 2014 Jan;73(1):69-77. doi: 10.1007/s00280-013-2318-3. Epub 2013 Nov 5.

Bortezomib-induced apoptosis in cultured pancreatic cancer cells is associated with ceramide production.

Author information

1
Department of Gastroenterology, Wuxi No. 2 People's Hospital, Wuxi, Jiangsu, China.

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.

PMID:
24190701
DOI:
10.1007/s00280-013-2318-3
[Indexed for MEDLINE]

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