Amphiregulin promotes resistance to gefitinib in nonsmall cell lung cancer cells by regulating Ku70 acetylation.
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.
Busser
Benoît
B
INSERM, U823, Institut Albert Bonniot, Grenoble, France.
Sancey
Lucie
L
Josserand
Véronique
V
Niang
Carole
C
Khochbin
Saadi
S
Favrot
Marie C
MC
Coll
Jean-Luc
JL
Hurbin
Amandine
A
D066258:Amphiregulin; D000818:Animals; D034961:Antigens, Nuclear / Q000096:biosynthesis*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D019008:Drug Resistance, Neoplasm; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006023:Glycoproteins / Q000494:pharmacology*; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D000072200:Ku Autoantigen; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D011799:Quinazolines / Q000494:pharmacology*; D013347:Subcellular Fractions; D000077337:Vorinostat; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C587848:AREG protein, human; D066258:Amphiregulin; D034961:Antigens, Nuclear; D000970:Antineoplastic Agents; C587849:Areg protein, mouse; D004268:DNA-Binding Proteins; D066255:EGF Family of Proteins; D006023:Glycoproteins; D006877:Hydroxamic Acids; D036341:Intercellular Signaling Peptides and Proteins; D011799:Quinazolines; D051028:bcl-2-Associated X Protein; D000077337:Vorinostat; D051548:Histone Acetyltransferases; D066246:ErbB Receptors; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen; D000077156:Gefitinib