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Insulin-Like Growth Factor-I Inhibits Cell Growth in the A549 Non-Small Lung Cancer Cell Line

Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St. Leonards, New South Wales, Australia

Address correspondence to: Dr. Janet Martin, Kolling Institute of Medical Research, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia. E-mail: janetlm{at}med.usyd.edu.au

Insulin-like growth factors (IGFs) are potent mitogenic and antiapoptotic factors for many cell types, including some normal and neoplastic lung cells in vitro. However, in this study we show that IGF-I, at concentrations of 10 ng/ml or greater, significantly inhibits DNA synthesis and cell proliferation in a human lung adenocarcinoma cell line, A549. Inhibition of DNA synthesis was completely reversed by an IGF-I receptor–neutralizing antibody, IR-3, indicating that IGF-I receptor activation is involved in its inhibitory effect. Attenuation of the p44/42 mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3'-kinase (PI 3'-kinase) pathways downstream of the IGF-I receptor using the inhibitors PD98059 and LY294002, respectively, partially reversed IGF-I–induced inhibition. Acute (2–60 min) and chronic (24 h) exposure of A549 cells to 100 ng/ml IGF-I resulted in sustained phosphorylation of Akt/protein kinase B downstream of PI 3'-kinase, whereas p44/42 MAPK phosphorylation was decreased in response to chronic exposure to IGF-I. An IGF-I dose-dependent increase in the cyclin-dependent kinase inhibitor p21^Cip1/WAF1 was also observed over 24 h of treatment. Collectively, these data suggest that IGF-I is growth inhibitory to A549 cells, possibly via sustained activation of the PI 3'-kinase signaling pathway, and induction of p21^Cip1/WAF1.

Abbreviations: anti-insulin like growth factor receptor I antibody, IR-3 • bovine serum albumin, BSA • cell-conditioned media, CM • 4,6-diamidino-2-phenylindole, DAPI • ethylenediaminetetraacetic acid, EDTA • epidermal growth factor, EGF • fetal calf serum, FCS • insulin-like growth factor, IGF • IGF-I receptor, IGF-IR • IGF-binding protein, IGFBP • insulin receptor substrate, IRS • [long Arg³]IGF-I, [LR³]IGF-I • mitogen-activated protein kinase, MAPK • phosphate-buffered saline, PBS • phosphatidylinositol 3'-kinase, PI 3'-kinase • phosphatase and tensin homolog deleted on chromosome ten, PTEN • protein phosphatase 2A, PP2A • radioimmunoassay, RIA • sodium dodecyl sulfate–polyacrylamide gel electrophoresis, SDS-PAGE • serum-free medium, SFM • Tris-HCl buffered saline, TBS • transforming growth factor-, TGF- • 12-O-tetradecanoylphorbol-13-acetate, TPA

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