Autocrine-mediated ErbB-2 kinase activation of STAT3 is required for growth factor independence of pancreatic cancer cell lines

摘要: Pancreatic ductal adenocarcinoma (PDAC) cell lines, MIA PaCa-2, and UK Pan-1, were used to investigate the role of ErbB2 in PDAC oncogenesis. Both these lines exhibit exogenous growth factor-independent proliferation that was attributed production autocrine factors and/or overexpression factor receptors. The phenotype displayed by dependent on kinase activity since treatment cells with tyrphostin AG879 prevented serum-free media (SFM) induction proliferation. We determined contributed aberrant cycle regulation through cyclin D1 levels suppression p21Cip1 p27Kip1. Inhibition led arrest marked an increased association p27Kip1 cdk2 reduced phosphorylated pRb. further observed constitutive STAT3 activation increase upon stimulating quiescent SFM. Inhibitors blocked activation, whereas inhibition EGFR a slight reduction activation. coimmunoprecipitated ErbB2. SFM stimulation caused STAT3, which kinase. Expression dominant negative SFM-stimulated PaCa-2 cells, suggesting is required for cells. Consistent this observation we found most tumor specimens (10 11) showed readily detected tumors (nine 11). believe findings indicate novel mechanism oncogenesis may suggest future therapeutic strategies PDAC.