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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Microtubule-Destabilizing Agents Induce Focal Adhesion Structure Disorganization and Anoikis in Cancer Cells

Centre de Recherche, Unité des Biotechnologies et de Bioingénierie, Centre Hospitalier Universitaire de Québec, Hôpital Saint-François d'Assise, Québec, Canada (R.G.D, A.P., J.S.F., C.R., M.-F.C., R.C.-G., E.P.); IMOTEP Inc., Québec City, Québec, Canada (J.L., C.R.); and Le Centre de Recherche en Cancérologie de l'Université Laval, Québec, Canada (J.H.)

Microtubule disruption provokes cytoskeleton and cell adhesion changes whose importance for apoptosis induction remains unclear. The present study focuses on the functional and the molecular adhesion kinetics that are induced by microtubule disruption-mediated apoptosis. We showed that antimicrotubules induce a biphasic sequence of adhesion response that precedes the onset of apoptosis and focal adhesion kinase hydrolysis. Antimicrotubules first induced an increase of the cellular adhesion paralleled by the raise of focal adhesion sites and actin contractility, which was followed by a sharp decrease of cell adhesion and disorganization of focal adhesion and actin stress fibers. The latter sequence of events ends by cell rounding, detachment from the extracellular matrix, and cell death. Microtubule-disrupting agents induced a sustained paxillin phosphorylation, before the activation of apoptosis, that requires the prior activation of extracellular signal-regulated kinase and p38 but not c-Jun NH₂-terminal kinase. Interestingly, integrin-linked kinase overexpression rescued the antimicrotubule-mediated loss of cell viability. Altogether, these results propound that antimicrotubule agents induce anoikis through the loss of focal adhesion structure integrity.

Address correspondence to: Dr. Eric Petitclerc, Centre de Recherche, Unité des Biotechnologies et de Bioingénierie, Centre Hospitalier Universitaire de Québec, Hôpital Saint-François d'Assise, 10 rue de l'Espinay, Québec, Québec, Canada G1L 3L5. E-mail: eric.petitclerc{at}crsfa.ulaval.ca