PMID- 19826407 OWN - NLM STAT- MEDLINE DCOM- 20101029 LR - 20211020 IS - 1525-0024 (Electronic) IS - 1525-0016 (Print) IS - 1525-0016 (Linking) VI - 18 IP - 3 DP - 2010 Mar TI - Amphiregulin promotes resistance to gefitinib in nonsmall cell lung cancer cells by regulating Ku70 acetylation. PG - 536-43 LID - 10.1038/mt.2009.227 [doi] AB - 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. FAU - Busser, Benoit AU - Busser B AD - INSERM, U823, Institut Albert Bonniot, Grenoble, France. FAU - Sancey, Lucie AU - Sancey L FAU - Josserand, Veronique AU - Josserand V FAU - Niang, Carole AU - Niang C FAU - Khochbin, Saadi AU - Khochbin S FAU - Favrot, Marie C AU - Favrot MC FAU - Coll, Jean-Luc AU - Coll JL FAU - Hurbin, Amandine AU - Hurbin A LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20091013 PL - United States TA - Mol Ther JT - Molecular therapy : the journal of the American Society of Gene Therapy JID - 100890581 RN - 0 (AREG protein, human) RN - 0 (Amphiregulin) RN - 0 (Antigens, Nuclear) RN - 0 (Antineoplastic Agents) RN - 0 (Areg protein, mouse) RN - 0 (DNA-Binding Proteins) RN - 0 (EGF Family of Proteins) RN - 0 (Glycoproteins) RN - 0 (Hydroxamic Acids) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 0 (Quinazolines) RN - 0 (bcl-2-Associated X Protein) RN - 58IFB293JI (Vorinostat) RN - EC 2.3.1.48 (Histone Acetyltransferases) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 3.6.4.12 (Xrcc6 protein, human) RN - EC 3.6.4.12 (Xrcc6 protein, mouse) RN - EC 4.2.99.- (Ku Autoantigen) RN - S65743JHBS (Gefitinib) SB - IM MH - Amphiregulin MH - Animals MH - Antigens, Nuclear/*biosynthesis MH - Antineoplastic Agents/pharmacology MH - *Apoptosis MH - Carcinoma, Non-Small-Cell Lung/*drug therapy/*metabolism MH - DNA-Binding Proteins/*biosynthesis MH - *Drug Resistance, Neoplasm MH - EGF Family of Proteins MH - ErbB Receptors/metabolism MH - Female MH - Gefitinib MH - Glycoproteins/*pharmacology MH - Histone Acetyltransferases/metabolism MH - Humans MH - Hydroxamic Acids/pharmacology MH - Intercellular Signaling Peptides and Proteins/*pharmacology MH - Ku Autoantigen MH - Lung Neoplasms/*drug therapy/*metabolism MH - Mice MH - Quinazolines/*pharmacology MH - Subcellular Fractions MH - Vorinostat MH - bcl-2-Associated X Protein/metabolism PMC - PMC2839437 EDAT- 2009/10/15 06:00 MHDA- 2010/10/30 06:00 PMCR- 2011/03/01 CRDT- 2009/10/15 06:00 PHST- 2009/10/15 06:00 [entrez] PHST- 2009/10/15 06:00 [pubmed] PHST- 2010/10/30 06:00 [medline] PHST- 2011/03/01 00:00 [pmc-release] AID - S1525-0016(16)32302-4 [pii] AID - 10.1038/mt.2009.227 [doi] PST - ppublish SO - Mol Ther. 2010 Mar;18(3):536-43. doi: 10.1038/mt.2009.227. Epub 2009 Oct 13.