Involvement of p38 mitogen-activated protein kinase in gemcitabine-induced apoptosis in human pancreatic cancer cells

In this study, we investigated the involvement of Akt and members of the mitogen-activated protein kinase (MAPK) superfamily, including ERK, JNK, and p38 MAPK, in gemcitabine-induced cytotoxicity in human pancreatic Cancer cells. We found that gemcitabine induces Apoptosis in PK-1 and PCI-43 human pancreatic Cancer cell lines. Gemcitabine specifically activated p38 MAPK in a dose- and time-dependent manner. A selective p38 MAPK Inhibitor, SB203580, significantly inhibited gemcitabine-induced Apoptosis in both cell lines, suggesting that phosphorylation of p38 MAPK may play a key role in gemcitabine-induced Apoptosis in pancreatic Cancer cells. A selective JNK Inhibitor, SP600125, failed to inhibit gemcitabine-induced Apoptosis in both cell lines. MKK3/6, an upstream activator of p38 MAPK, was phosphorylated by gemcitabine, indicating that the MKK3/6-p38 MAPK signaling pathway is indeed involved in gemcitabine-induced Apoptosis. Furthermore, gemcitabine-induced cleavage of the Caspase substrate poly(ADP-ribose) polymerase was inhibited by pretreatment with SB203580, suggesting that activation of p38 MAPK by gemcitabine induces Apoptosis through Caspase signaling. These results together suggest that gemcitabine-induced Apoptosis in human pancreatic Cancer cells is mediated by the MKK3/6-p38 MAPK-caspase signaling pathway. Further, these results lead us to suggest that p38 MAPK should be investigated as a novel molecular target for human pancreatic Cancer therapies.