Adenovirus-mediated gene transfer of caspase-8 sensitizes human adenocarcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand

Abstract

Resistance to apoptosis has been implicated in the poor response of cancer cells to various anti-tumor agents. Caspase-8 is a family member of executioner caspases associated with tumor necrosis factor (TNF) family death receptors-mediated apoptotic signaling cascade. In this study, to specify caspase-8-mediated apoptotic activity, we examined the anti-tumor effect of adenoviral vector expressing caspase-8 (Adv-caspase-8) in combination with TNF-related apoptosis-inducing ligand (TRAIL) which induces specifically caspase-8 activation. First, we demonstrated that expression procaspase-8 is related to apoptosis sensitivity to TRAIL in pancreatic and colonic cancer cells. In human pancreatic cancer cell line Panc1 which demonstrates low expression of procaspase-8, Adv-caspase-8 transfection strongly augmented TRAIL-induced apoptosis. Adv-caspase-8 similarly enhanced the susceptibility of human colonic cancer cell line Colo320DM to TRAIL. These results suggest that Adv-caspase-8 may be a good combination partner of TRAIL and enables TRAIL to be a more potent anticancer agent in a wide range of adenocarcinoma cells which demonstrate low expression of caspase-8.