ErbB1 activity is essential for androgen induced proliferation and anti-apoptotic effect of prostate cancer: Investigations in in vitro and in vivo models.

N Torring, Ph.D. a,b, F Dagneas-Hansen, Ph.D, c, BS Soerensen, Ph.D, b, E Nexoe, MD, b, and N Hynes, Ph.D, a

a Friedrich Miescher Institute, Basel, Switzerland, b Department of Clinical Biochemistry, Aarhus University Hospital, cDepartment of Clinical Microbiology and Immunology, Aarhus University, Denmark

Androgen plays a critical role in controlling growth and survival of prostate cancer cells, by increasing cellular proliferation and inhibiting apoptosis, but the exact mechanisms underlying these effects are poorly described. As a model for androgen induced growth and anti apoptosis in prostate cancer we used the androgen sensitive LNCaP cells and the androgen responsive prostate cancer xenograft CWR22 passed in SCID mice. In these models we analyzed the expression and activity of the tyrosine kinase receptors ErbB1-3, the expression of the ligands activating ErbB1 from the epidermal growth factor (EGF) network, and the impact of ErbB1 inhibition on androgen induced proliferation and anti-apoptosis. Androgen selectively increases the expression and the activity of ErbB1 mRNA and protein. Blocking the ErbB1 activity by a specific tyrosine kinase inhibitor CGP59326, abrogates the androgen induced proliferation in LNCaP cells without affecting cell viability, determined by MTT assay after 96 hrs of androgen exposure. Apoptosis induced by phosphatidylinositol 3´ kinase inhibitor LY294002 in serum starved LNCaP cells was attenuated by androgen, demonstrated Western Blot analysis of PARP cleavage. This rescue from apoptosis was profoundly inhibited by CGP59326. These results indicate that androgen increases the activity of the EGF-network in prostate cancer by increasing ErbB1 expression, and that this activity of this tyrosine kinase receptor is essential for androgen induced proliferation and survival of prostate cancer cells.

KEY WORDS: Prostate cancer, ErbB1, androgen, proliferation, apoptosis.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Apoptosis - Molecular Mechanisms.