Insulin-like growth factor-I inhibits cell growth in the a549 non-small lung cancer cell line.
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, alphaIR-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).
Kodama
Yuzo
Y
Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St. Leonards, New South Wales, Australia.
Baxter
Robert C
RC
Martin
Janet L
JL
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000187:drug effects / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1 / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
D002867:Chromones; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004247:DNA; D004791:Enzyme Inhibitors; D005419:Flavonoids; D018972:Insulin-Like Growth Factor Binding Protein 3; D007334:Insulin-Like Growth Factor I; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; C493956:CDKN1A protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one