¹University Children's Hospital, Ulm, Germany

Correspondence: Dr S Fulda, University Children's Hospital, Eythstr. 24, D-89075 Ulm, Germany. E-mail: simone.fulda@uniklinik-ulm.de

Received 27 October 2005; Revised 2 May 2006; Accepted 19 May 2006; Published online 10 July 2006.

Abstract

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapy because of its relative tumor selectivity. However, many cancers including pancreatic cancer remain resistant towards TRAIL. To develop TRAIL for cancer therapy of pancreatic carcinoma, it will therefore be pivotal to elucidate the molecular mechanisms of TRAIL resistance. Here, we identify X-linked inhibitor of apoptosis (XIAP) as a regulator of TRAIL sensitivity in pancreatic carcinoma cells. Full activation of effector caspases, loss of mitochondrial membrane potential and cytochrome c release following TRAIL treatment were markedly impaired in pancreatic carcinoma cell lines, which poorly responded to TRAIL (PaTuII, PancTu1, ASPC1, DanG), compared to TRAIL-sensitive Colo357 pancreatic carcinoma cells. Stable downregulation of XIAP by RNA interference significantly reduced survival and enhanced TRAIL-induced apoptosis in pancreatic carcinoma cells. Also, downregulation of XIAP significantly increased CD95-induced cell death. Importantly, knockdown of XIAP strongly inhibited clonogenicity of pancreatic cancer cells treated with TRAIL indicating that XIAP promotes clonogenic survival of pancreatic carcinoma cells. Thus, our findings for the first time indicate that targeting XIAP represents a promising strategy to enhance the antitumor activity of TRAIL in pancreatic cancer, which has important clinical implications.