Inhibition of glycogen synthase kinase-3 activity triggers an apoptotic response in pancreatic cancer cells through JNK-dependent mechanisms.
Recent evidences suggest that the activity of glycogen synthase kinase-3 (GSK3) contributes to the tumorigenic potential of pancreatic cancer cells through modulation of cell proliferation and survival. However, further investigations are needed to identify GSK3-dependent mechanisms involved in the control of pancreatic cancer cell proliferation and survival. This study was undertaken to provide further support for a role of GSK3 in pancreatic cancer cell growth as well as to identify new cellular and molecular mechanisms involved. Herein, we demonstrate that prolonged inhibition of GSK3 triggers an apoptotic response only in human pancreatic cancer cells but not in human non-transformed pancreatic epithelial cells. We show that prolonged inhibition of GSK3 activity increases Bim messenger RNA and protein expressions. Moreover, we provide evidence that activation of the c-jun N-terminal kinase (JNK) pathway is necessary for the GSK3 inhibition-mediated increase in Bim expression and apoptotic response. Finally, we demonstrate that concomitant inhibition of GSK3 potentiates the death ligand-induced apoptotic response in pancreatic cancer cells but not in non-transformed pancreatic epithelial cells and that this effect also requires JNK activity. Considering that different approaches leading to stimulation of death receptor signaling are under clinical trials for treatment of unresectable or metastatic pancreatic cancer, inhibition of GSK3 could represent an attractive new avenue to improve their effectiveness.
Service de Gastroentérologie, Département de Médecine, Université de Sherbrooke, 3001, 12e avenue nord, Sherbrooke, Québec, Canada.
Benoît
B
Marchand
Isabelle
I
Tremblay
Sébastien
S
Cagnol
Marie-Josée
MJ
Boucher
D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008301:Maleimides / Q000494:pharmacology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D053218:Receptors, Death Domain / Q000378:metabolism
D000873:Anthracenes; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C473711:Chir 99021; D007211:Indoles; D008301:Maleimides; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D011743:Pyrimidines; D012333:RNA, Messenger; D053218:Receptors, Death Domain; C417521:SB 216763; C432165:pyrazolanthrone; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3