Journal Article

Cell cycle activation in lung adenocarcinoma cells by the ErbB3/phosphatidylinositol 3-kinase/Akt pathway

Gunamani Sithanandam, George T. Smith, Akira Masuda, Takashi Takahashi, Lucy M. Anderson and Laura W. Fornwald

in Carcinogenesis

Volume 24, issue 10, pages 1581-1592
Published in print October 2003 | ISSN: 0143-3334
Published online October 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgg125
Cell cycle activation in lung adenocarcinoma cells by the ErbB3/phosphatidylinositol 3-kinase/Akt pathway

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Although ErbB3, a member of the epidermal growth factor receptor family, has been implicated in mammary tumorigenesis, investigation of its role in lung tumorigenesis has been limited. We found that ErbB3 was present at high levels in five of seven human lung adenocarcinoma cell lines examined, along with its ligands, heregulins α and β, whereas ErbB3 was absent from HPL1D, a non- transformed cell line from human pulmonary peripheral epithelium. Interactions and effects of ErbB3 were studied in detail in adenocarcinoma lines H441 and H1373. Complexes containing phosphorylated ErbB2, phosphorylated ErbB3 and the p85 regulatory subunit of phosphoinositidyl 3-kinase were detected by co-immunoprecipitation experiments and were present constitutively even in the absence of serum-stimulated cell division. Serum treatment increased the pErbB3/p85 complexes and also stimulated phosphorylation of Akt and GSK3β, increase in cyclin D1 and cell cycle progression, and these events were blocked by the Akt activation inhibitor LY294002. An ErbB3-specific antisense oligonucleotide reduced amounts of ErbB3 protein and p85 complex in both cell lines, and significantly suppressed cell proliferation. These results together suggest involvement of ErbB3 in growth of lung adenocarcinomas, through activation of phosphoinositidyl 3 kinase and Akt, inactivation of GSK3β and stabilization of cyclin D1 for cell cycle maintenance. It could be a useful therapeutic target.

Keywords: EGFR, epidermal growth factor receptor; FACS, fluorescence-activated cell sorting; HRGs, heregulins; PI3K, phosphatidylinositol 3-kinase

Journal Article.  8067 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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