title: TRAIL promotes membrane blebbing, detachment and migration of cells displaying a dysfunctional intrinsic pathway of apoptosis.
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 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.
authors.affiliation: Department of Cell Biology, University of Geneva, Sciences III, 30 quai Ernest Ansermet, 1211 Geneva 4, Switzerland.
authors.forename: Syam Prakash
authors.initials: SP
authors.lastname: Somasekharan
authors.forename: Michal
authors.initials: M
authors.lastname: Koc
authors.forename: Alexandre
authors.initials: A
authors.lastname: Morizot
authors.forename: Olivier
authors.initials: O
authors.lastname: Micheau
authors.forename: Poul H B
authors.initials: PH
authors.lastname: Sorensen
authors.forename: Olivier
authors.initials: O
authors.lastname: Gaide
authors.forename: Ladislav
authors.initials: L
authors.lastname: Andera
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Martinou
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; D053148:Caspase 3