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Published on: April 6, 2016
Insulin-like growth factor-I inhibits cell growth in the a549 non-small lung cancer cell line
Yuzo Kodama1, Robert C Baxter, Janet L Martin
1Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St. Leonards, New South Wales, Australia.
Abstract:
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).
Insights
Insulin-like growth factor-I (IGF-I) inhibits A549 lung cancer cell growth by activating the PI 3-kinase pathway and increasing p21 protein. This unexpected finding suggests IGF-I may have therapeutic potential in lung adenocarcinoma.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Insulin-like growth factors (IGFs) are known mitogenic and antiapoptotic factors.
- Some lung cells, both normal and neoplastic, respond mitogenically to IGFs in vitro.
Purpose of the Study:
- To investigate the effect of IGF-I on DNA synthesis and proliferation in a human lung adenocarcinoma cell line (A549).
- To elucidate the signaling pathways involved in IGF-I's action on A549 cells.
Main Methods:
- A549 cells were treated with varying concentrations of IGF-I.
- IGF-I receptor activation was blocked using alphaIR-3 antibody.
- Specific pathway inhibitors (PD98059, LY294002) were used to attenuate MAPK and PI 3-kinase pathways.
- Cellular signaling proteins (Akt, p44/42 MAPK) and cell cycle inhibitors (p21Cip1/WAF1) were analyzed via Western blotting.
Main Results:
- IGF-I significantly inhibited DNA synthesis and proliferation in A549 cells at concentrations ≥10 ng/ml.
- The inhibitory effect was reversed by an IGF-I receptor-neutralizing antibody.
- Inhibition was partially reversed by PD98059 and LY294002, implicating both MAPK and PI 3-kinase pathways.
- Sustained Akt phosphorylation and decreased p44/42 MAPK phosphorylation were observed with chronic IGF-I exposure.
- IGF-I induced a dose-dependent increase in p21(Cip1/WAF1) levels.
Conclusions:
- IGF-I exhibits a growth-inhibitory effect on A549 lung adenocarcinoma cells.
- This inhibition appears mediated by sustained activation of the PI 3-kinase/Akt pathway and induction of the p21(Cip1/WAF1) cell cycle inhibitor.
- The findings suggest a complex role for IGF-I signaling in lung cancer, potentially offering therapeutic avenues.
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