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.