Lung Cancer (2008) 60, 355—365 available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/lungcan TRAIL-induced survival and proliferation of SCLC cells is mediated by ERK and dependent on TRAIL-R2/DR5 expression in the absence of caspase-8 Larisa L. Belyanskaya a , Algirdas Ziogas c , Sally Hopkins-Donaldson b , Stefanie Kurtz b , Hans-Uwe Simon c , Rolf Stahel b , Uwe Zangemeister-Wittke c,* a Laboratory for Material - Biology Interaction, Swiss Federal Laboratories for Materials Testing and Research (EMPA), St. Gallen, Switzerland b Laboratory of Molecular Oncology, Department of Oncology, University of Zuerich, Switzerland c Institute of Pharmacology, University of Bern, Friedbuehlstrasse 49, CH-3010 Bern, Switzerland Received 24 August 2007; received in revised form 2 November 2007; accepted 6 November 2007 KEYWORDS SCLC; TRAIL; Caspase-8; ERK1/2; Cell death/proliferation; IFN- Summary Small cell lung cancer (SCLC) is characterized by an aggressive phenotype and acquired resistance to a broad spectrum of anticancer agents. TNF-related apoptosis-inducing ligand (TRAIL) has been considered as a promising candidate for safe and selective induction of tumor cell apoptosis without toxicity to normal tissues. Here we report that TRAIL failed to induce apoptosis in SCLC cells and instead resulted in an up to 40% increase in proliferation. TRAIL-induced SCLC cell proliferation was mediated by extracellular signal-regulated kinase 1 and 2, and dependent on the expression of surface TRAIL-receptor 2 (TRAIL-R2) and lack of caspase-8, which is frequent in SCLC. Treatment of SCLC cells with interferon- (IFN-) restored caspase-8 expression and facilitated TRAIL-induced apoptosis. The overall loss of cell proliferation/viability upon treatment with the IFN--TRAIL combination was 70% compared to TRAIL-only treated cells and more than 30% compared to untreated cells. Similar results were Abbreviations: DISC, death-inducing signaling complex; ERK1/2, extracellular signal-regulated kinase 1 and 2; FADD, Fas-associated death domain; FLICE, FADD-like ICE; FLIP, FLICE-inhibitory protein; IFN-, interferon-; MEK, mitogen-activated ERK kinase; NF-B, nuclear factor kappa B; PI3K, phosphatidylinositol 3-kinase; SCLC, small cell lung cancer; TNF, tumor necrosis factor; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; TRAIL-R, TRAIL-receptor. ∗ Corresponding author. Tel.: +41 31 632 3290; fax: +41 31 632 4992. E-mail address: uwe.zangemeister@pki.unibe.ch (U. Zangemeister-Wittke). 0169-5002/$ — see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2007.11.005