TRAIL promotes membrane blebbing, detachment and migration of cells displaying a dysfunctional intrinsic pathway of apop
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ORIGINAL PAPER
TRAIL promotes membrane blebbing, detachment and migration of cells displaying a dysfunctional intrinsic pathway of apoptosis Syam Prakash Somasekharan • Michal Koc • Alexandre Morizot Olivier Micheau • Poul H. B. Sorensen • Olivier Gaide • Ladislav Andera • Jean-Claude Martinou
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Ó Springer Science+Business Media New York 2012
Abstract Recently, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) has been shown to be a potential candidate for cancer therapy. TRAIL induces apoptosis in various cancer cells but not in normal tissues. Here we show that HCT116 and SW480 cells with a deficient mitochondrial apoptotic pathway were resistant to TRAIL-induced apoptosis, whereas HCT116 and SW480 cells with a functional mitochondrial apoptotic pathway underwent apoptosis upon exposure to TRAIL. Surprisingly, TRAIL induced phenotypic changes in cells with a dysfunctional mitochondrial apoptotic pathway, including membrane blebbing and a transient loss of adhesion Electronic supplementary material The online version of this article (doi:10.1007/s10495-012-0782-6) contains supplementary material, which is available to authorized users. S. P. Somasekharan J.-C. Martinou (&) Department of Cell Biology, University of Geneva, Sciences III, 30 quai Ernest Ansermet, 1211 Geneva 4, Switzerland e-mail: [email protected] S. P. Somasekharan P. H. B. Sorensen Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, Canada S. P. Somasekharan P. H. B. Sorensen Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada M. Koc L. Andera Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic A. Morizot O. Micheau INSERM, UMR866, 21079 Dijon, France O. Gaide Department of Dermatology-Venereology, Geneva University Hospital, Michel-Servet 1, Geneva, Switzerland
properties to the substratum. Accordingly, TRAIL stimulated the ability of these cells to migrate. This behavior was the consequence of a transient TRAIL-induced ROCK1 cleavage. In addition, we report that Bax-deficient HCT116 cells exposed to TRAIL for a prolonged period lost their sensitivity to TRAIL as a result of downregulation of TRAIL receptor expression, and became resistant to combination of TRAIL and other drugs such as MG-132 and bortezomib. These findings may have important consequences for TRAIL anti-cancer therapy. Keywords TRAIL Membrane blebbing ROCK1 HCT116 Bax-/- Cancer cell migration Drug resistance Bortezomib Proteasome Abbreviations TRAIL Tumor necrosis factor (TNF)-related apoptosis-inducing ligand TNFR1 Tumor necrosis factor receptor-1 DISC Death inducing signaling complex TRAIL-R1 TRAIL receptor-1 TRAIL-R2 TRAIL receptor-2 MLC Myosin light chain ROCK1 Rho-associated, coiled-coil containing protein kinase 1 IAPs Inhibitors of apoptosis XIAP X-linked inhibitor of apoptosis
Introduction Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) is a type 2 t
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