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.
OBJECTIVE
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.


METHODS
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.
Pino
Maria S
MS
Division of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy.
Balsamo
Michele
M
Di Modugno
Francesca
F
Mottolese
Marcella
M
Alessio
Massimo
M
Melucci
Elisa
E
Milella
Michele
M
McConkey
David J
DJ
Philippar
Ulrike
U
Gertler
Frank B
FB
Natali
Pier Giorgio
PG
Nisticò
Paola
P
D000230:Adenocarcinoma / Q000378:metabolism / Q000628:therapy*; D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004848:Epithelium / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008648:Mesoderm / Q000378:metabolism; D008840:Microfilament Proteins / Q000737:chemistry* / Q000502:physiology*; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000628:therapy*; D010641:Phenotype; D011799:Quinazolines / Q000494:pharmacology
C511939:Enah protein, human; D008840:Microfilament Proteins; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors