Amphiregulin promotes resistance to gefitinib in nonsmall cell lung cancer cells by regulating Ku70 acetylation.

Benoît Busser 1 Lucie Sancey 1 Véronique Josserand 1 Carole Niang 1 Saadi Khochbin 2 Marie Favrot 3 Jean-Luc Coll 4 Amandine Hurbin 4
1 INSERM U823 - Institut d'oncologie/développement Albert Bonniot de Grenoble
2 INSERM U823, équipe 6 (Epigénétique et Signalisation Cellulaire)
INSERM U823 - Institut d'oncologie/développement Albert Bonniot de Grenoble
3 CIB - Centre d'innovation en biologie
4 INSERM U823, équipe 5 (cibles diagnostiques ou thérapeutiques et vectorisation de drogues dans le cancer du poumon)
INSERM U823 - Institut d'oncologie/développement Albert Bonniot de Grenoble
Abstract : Multiple molecular resistance mechanisms reduce the efficiency of receptor tyrosine kinase inhibitors such as gefitinib in non-small cell lung cancer (NSCLC). We previously demonstrated that amphiregulin (Areg) inhibits gefitinib-induced apoptosis in NSCLC cells by inactivating the proapoptotic protein BAX. In this part of the investigation, we studied the molecular mechanisms leading to BAX inactivation. We show that Areg prevents gefitinib-mediated acetylation of Ku70. This augments the BAX-Ku70 interaction and therefore prevents BAX-mediated apoptosis. Accordingly, Areg or Ku70 knock down restore BAX activation and apoptosis in gefitinib-treated H358 cells in vitro. In addition, overexpression of the histone acetyltransferase (HAT) CREB-binding protein (CBP) or treatments with histone deacetylase (HDAC) inhibitors sensitize H358 cells to gefitinib. Moreover, a treatment with vorinostat, a HDAC inhibitor strongly sensitized tumors to gefitinib in vivo. These findings suggest new prospects in combining both HDAC and epidermal growth factor receptor inhibitors for the treatment of NSCLC.
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Article dans une revue
Molecular Therapy, Nature Publishing Group, 2010, 18 (3), pp.536-43. 〈10.1038/mt.2009.227〉
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http://www.hal.inserm.fr/inserm-00425467
Contributeur : Amandine Hurbin <>
Soumis le : mercredi 21 octobre 2009 - 15:27:42
Dernière modification le : mercredi 10 janvier 2018 - 10:12:02
Document(s) archivé(s) le : mardi 15 juin 2010 - 21:37:21

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Benoît Busser, Lucie Sancey, Véronique Josserand, Carole Niang, Saadi Khochbin, et al.. Amphiregulin promotes resistance to gefitinib in nonsmall cell lung cancer cells by regulating Ku70 acetylation.. Molecular Therapy, Nature Publishing Group, 2010, 18 (3), pp.536-43. 〈10.1038/mt.2009.227〉. 〈inserm-00425467〉

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