Bcl-xL inhibition by molecular-targeting drugs sensitizes human pancreatic cancer cells to TRAIL

Abstract

// Yoko Hari 1, 2 , Nanae Harashima 2 , Yoshitsugu Tajima 1 , Mamoru Harada 2 1 Department of Surgery, Shimane University Faculty of Medicine, Shimane, Japan 2 Department of Immunology, Shimane University Faculty of Medicine, Shimane, Japan Correspondence to: Mamoru Harada, e-mail: haramamo@med.shimane-u.ac.jp Keywords: pancreatic cancer, TRAIL, apoptosis, Bcl-2, Bcl-xL Received: June 21, 2015      Accepted: October 06, 2015      Published: October 19, 2015 ABSTRACT Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various types of cancer cells without damaging normal cells. However, in terms of pancreatic cancer, not all cancer cells are sensitive to TRAIL. In this study, we examined a panel of human pancreatic cancer cell lines for TRAIL sensitivity and investigated the effects of Bcl-2 family inhibitors on their response to TRAIL. Both ABT-263 and ABT-737 inhibited the function of Bcl-2, Bcl-xL, and Bcl-w. Of the nine pancreatic cancer cell lines tested, six showed no or low sensitivity to TRAIL, which correlated with protein expression of Bcl-xL. ABT-263 significantly sensitized four cell lines (AsPC-1, Panc-1, CFPAC-1, and Panc10.05) to TRAIL, with reduced cell viability and increased apoptosis. Knockdown of Bcl-xL, but not Bcl-2, by siRNA transfection increased the sensitivity of AsPC-1 and Panc-1 cells to TRAIL. ABT-263 treatment had no effect on protein expression of Bcl-2, Bcl-xL, or c-FLIPs. In Panc-1 cells, ABT-263 increased the surface expression of death receptor (DR) 5; the NF-κB pathway, but not endoplasmic reticulum stress, participated in the increase. In xenograft mouse models, the combination of TRAIL and ATB-737 suppressed the in vivo tumor growth of AsPC-1 and Panc-1 cells. These results indicate that Bcl-xL is responsible for TRAIL resistance in human pancreatic cancer cells, and that Bcl-2 family inhibitors could represent promising reagents to sensitize human pancreatic cancers in DR-targeting therapy.