Mitochondrial inside-out signalling during alkylating agent-induced anoikis.
Exposure of epithelial respiratory cells to the alkylating agent, mechlorethamine (HN2), induces anoikis initiated by mitochondrial depolarization and caspase-2 activation. The mechanisms of disruption of cell interactions were investigated and expression of integrins, E-cadherin, and actin were therefore studied after HN2 treatment. In the adherent cells, an early disruption of F-actin occurred associated with cell rounding. Inhibitors of caspase-2 resulted in attenuating of the decline of adhesion proteins and microfilaments. HN2-induced down-regulation of beta1 integrin, E-cadherin expression and F-actin pattern occurred in detached cells but were efficiently prevented by inhibitors of mitochondrial permeabilization. Moreover, inhibiting mitochondrial depolarization improved significantly both cell survival and capacity of detached cells to re-adhere. These findings confirm the pro-survival integrins and E-cadherin mediated signalling pathway. The central role of mitochondria in HN2-induced cell detachment is reinforced, suggesting that mitochondria acts as a key executor of reduced cell adherence during anoikis and could be responsible of an inside-out signalling. Present data support the potential of these therapeutics, generated via the inhibition of mitochondrial depolarization, as protectors against the alkylating agent lesions.
Sourdeval
Matthieu
M
Laboratoire de Genetique et Biologie Cellulaire, UMR 8159, Universite de Versailles St Quentin en Yvelines, Batiment Buffon, 45 Avenue des Etats-Unis, 78035 Versailles Cedex, France. matthieu.sourdeval@uvsq.fr
Boisvieux-Ulrich
Emmanuelle
E
Gendron
Marie-Claude
MC
Marano
Francelyne
F
D000477:Alkylating Agents / Q000494:pharmacology*; D023102:Anoikis / Q000187:drug effects*; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D005434:Flow Cytometry; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011480:Protease Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*
D000477:Alkylating Agents; D015820:Cadherins; D016023:Integrins; D011480:Protease Inhibitors