Human Mena+11a isoform serves as a marker of epithelial phenotype and sensitivity to epidermal growth factor receptor inhibition in human pancreatic cancer cell lines.

TitleHuman Mena+11a isoform serves as a marker of epithelial phenotype and sensitivity to epidermal growth factor receptor inhibition in human pancreatic cancer cell lines.
Publication TypeJournal Article
Year of Publication2008
AuthorsPino, MS, Balsamo, M, Di Modugno, F, Mottolese, M, Alessio, M, Melucci, E, Milella, M, McConkey, DJ, Philippar, U, Gertler, FB, Natali, PG, Nistico, P
JournalClin Cancer Res
Volume14
Issue15
Pagination4943-50
Date Published2008 Aug 1
ISSN1078-0432
KeywordsAdenocarcinoma, Adult, Aged, Cell Line, Tumor, Cell Proliferation, Epithelium, Humans, Mesoderm, Microfilament Proteins, Middle Aged, Pancreatic Neoplasms, Phenotype, Quinazolines, Receptor, Epidermal Growth Factor
Abstract

PURPOSE: hMena, member of the enabled/vasodilator-stimulated phosphoprotein family, is a cytoskeletal protein that is involved in the regulation of cell motility and adhesion. The aim of this study was to determine whether or not the expression of hMena isoforms correlated with sensitivity to EGFR tyrosine kinase inhibitors and could serve as markers with potential clinical use.EXPERIMENTAL DESIGN: Human pancreatic ductal adenocarcinoma cell lines were characterized for in vitro sensitivity to erlotinib, expression of HER family receptors, markers of epithelial to mesenchymal transition, and expression of hMena and its isoform hMena(+11a). The effects of epidermal growth factor (EGF) and erlotinib on hMena expression as well as the effect of hMena knockdown on cell proliferation were also evaluated.RESULTS: hMena was detected in all of the pancreatic tumor cell lines tested as well as in the majority of the human tumor samples [primary (92%) and metastatic (86%)]. Intriguingly, in vitro hMena(+11a) isoform was specifically associated with an epithelial phenotype, EGFR dependency, and sensitivity to erlotinib. In epithelial BxPC3 cells, epidermal growth factor up-regulated hMena/hMena(+11a) and erlotinib down-regulated expression. hMena knockdown reduced cell proliferation and mitogen-activated protein kinase and AKT activation in BxPC3 cells, and promoted the growth inhibitory effects of erlotinib.CONCLUSIONS: Collectively, our data indicate that the hMena(+11a) isoform is associated with an epithelial phenotype and identifies EGFR-dependent cell lines that are sensitive to the EGFR inhibitor erlotinib. The availability of anti-hMena(+11a)-specific probes may offer a new tool in pancreatic cancer management if these results can be verified prospectively in cancer patients.

DOI10.1158/1078-0432.CCR-08-0436
Alternate JournalClin. Cancer Res.
PubMed ID18676769
PubMed Central IDPMC2586967
Grant List1U54 CA112967-03 / CA / NCI NIH HHS / United States
GM58801 / GM / NIGMS NIH HHS / United States
R01 GM058801-01 / GM / NIGMS NIH HHS / United States
R01 GM058801-09 / GM / NIGMS NIH HHS / United States