AIM: We have previously reported that 15-deoxy-delta-prostaglandin J2 (15d-PGJ2), a potent ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), induces caspase-mediated apoptosis in human pancreatic cancer cell lines. Mitogen-activated protein kinases (MAPKs) are known to regulate apoptosis in various cancers. The purpose of this study was to investigate the role of MAPKs (ERK, JNK, and p38) in 15d-PGJ2-induced pancreatic cancer cell apoptosis. METHODOLOGY: The effect of 15d-PGJ2 on MAPK activity was investigated by kinase assays using the human pancreatic cancer cell line MIA PaCa-2. Western blot analysis was performed to analyze phosphorylation of MAPKs, activation of caspases and poly ADP-ribose polymerase (PARP) cleavage. Apoptosis was evaluated by caspase-3 enzymatic activity and DNA fragmentation assay. RESULTS: 15d-PGJ2 activated all 3 MAPKs in a dose- and time-dependent fashion. SB202190, an inhibitor of p38, prevented 15d-PGJ2-induced activation of caspase-8, -9, and -3 and significantly decreased apoptosis. This effect was potentiated by SP600125, an inhibitor of JNK, although SP600125 alone had no significant effect on 15d-PGJ2-induced apoptosis. In contrast, PD98059, an inhibitor of MEK, significantly increased sensitivity to 15d-PGJ2-induced apoptosis. CONCLUSIONS: 15d-PGJ2 stimulates proapoptotic and antiapoptotic MAPK pathways. Sensitivity to 15d-PGJ2-induced apoptosis is increased by ERK inhibition but decreased by inhibition of p38.
AIM: We have previously reported that 15-deoxy-delta-prostaglandin J2 (15d-PGJ2), a potent ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), induces caspase-mediated apoptosis in humanpancreatic cancer cell lines. Mitogen-activated protein kinases (MAPKs) are known to regulate apoptosis in various cancers. The purpose of this study was to investigate the role of MAPKs (ERK, JNK, and p38) in 15d-PGJ2-induced pancreatic cancer cell apoptosis. METHODOLOGY: The effect of 15d-PGJ2 on MAPK activity was investigated by kinase assays using the humanpancreatic cancer cell line MIA PaCa-2. Western blot analysis was performed to analyze phosphorylation of MAPKs, activation of caspases and poly ADP-ribose polymerase (PARP) cleavage. Apoptosis was evaluated by caspase-3 enzymatic activity and DNA fragmentation assay. RESULTS:15d-PGJ2 activated all 3 MAPKs in a dose- and time-dependent fashion. SB202190, an inhibitor of p38, prevented 15d-PGJ2-induced activation of caspase-8, -9, and -3 and significantly decreased apoptosis. This effect was potentiated by SP600125, an inhibitor of JNK, although SP600125 alone had no significant effect on 15d-PGJ2-induced apoptosis. In contrast, PD98059, an inhibitor of MEK, significantly increased sensitivity to 15d-PGJ2-induced apoptosis. CONCLUSIONS:15d-PGJ2 stimulates proapoptotic and antiapoptotic MAPK pathways. Sensitivity to 15d-PGJ2-induced apoptosis is increased by ERK inhibition but decreased by inhibition of p38.
Authors: Callum M Sloss; Fang Wang; Rong Liu; Lijun Xia; Michael Houston; David Ljungman; Michael A Palladino; James C Cusack Journal: Clin Cancer Res Date: 2008-08-15 Impact factor: 12.531
Authors: Heather E Ferguson; Thomas H Thatcher; Keith C Olsen; Tatiana M Garcia-Bates; Carolyn J Baglole; R M Kottmann; Emily R Strong; Richard P Phipps; Patricia J Sime Journal: Am J Physiol Lung Cell Mol Physiol Date: 2009-09-04 Impact factor: 5.464