PMID- 19826406
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 BAX inhibition and resistance to gefitinib in 
      non-small-cell lung cancers.
PG  - 528-35
LID - 10.1038/mt.2009.226 [doi]
AB  - Molecular resistance mechanisms affecting the efficiency of receptor tyrosine 
      kinase inhibitors such as gefitinib in non-small-cell lung cancer (NSCLC) cells 
      are not fully understood. Amphiregulin (Areg) overexpression has been proposed to 
      predict NSCLC resistance to gefitinib and we have established that 
      Areg-overexpressing H358 NSCLC cells resist apoptosis. Here, we demonstrate that 
      Areg prevents gefitinib-induced apoptosis in NSCLC cells. We show that H358 cells 
      are resistant to gefitinib in contrast to H322 cells, which do not overexpress 
      Areg. Inhibition of Areg expression by small-interfering RNAs (siRNAs) restores 
      gefitinib sensitivity in H358 cells, whereas addition of recombinant Areg confers 
      resistance in H322 cells. Areg knockdown overcomes resistance to gefitinib and 
      induced apoptosis in NSCLC H358 cells in vitro and in vivo. Under gefitinib 
      treatment, Areg decreases the expression of the proapoptotic protein BAX, 
      inhibits its conformational change and its mitochondrial translocation. Thus, in 
      the presence of Areg, gefitinib-mediated apoptosis is reduced because BAX is 
      sequestered in the cytoplasm. This suggests that treatments using epidermal 
      growth factor receptor (EGFR) inhibitors may be poorly efficient in patients with 
      elevated levels of Areg. These findings indicate the need for inhibition of Areg 
      to enhance the efficiency of the EGFR inhibitors in patients suffering 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 - 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 (Antineoplastic Agents)
RN  - 0 (Areg protein, mouse)
RN  - 0 (EGF Family of Proteins)
RN  - 0 (Glycoproteins)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Quinazolines)
RN  - 0 (bcl-2-Associated X Protein)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - S65743JHBS (Gefitinib)
SB  - IM
MH  - Amphiregulin
MH  - Animals
MH  - Antineoplastic Agents/pharmacology
MH  - *Apoptosis
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy/*metabolism
MH  - Cell Line, Tumor
MH  - Cytoplasm/metabolism
MH  - *Drug Resistance, Neoplasm
MH  - EGF Family of Proteins
MH  - ErbB Receptors/metabolism
MH  - Gefitinib
MH  - Glycoproteins/*pharmacology
MH  - Humans
MH  - Intercellular Signaling Peptides and Proteins/*pharmacology
MH  - Lung Neoplasms/*drug therapy/*metabolism
MH  - Mice
MH  - Mitochondria/metabolism
MH  - Quinazolines/pharmacology
MH  - bcl-2-Associated X Protein/*metabolism
PMC - PMC2839434
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)32301-2 [pii]
AID - 10.1038/mt.2009.226 [doi]
PST - ppublish
SO  - Mol Ther. 2010 Mar;18(3):528-35. doi: 10.1038/mt.2009.226. Epub 2009 Oct 13.