HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathwaythe University of Texas, M. D. Anderson Cancer Center, Houston, Texas United States
AIM: Prostate cancer progresses from androgen sensitive to an androgen-infractory stage. The mechanism for the progression to androgen independence is not completely understood. In this study, we examined whether Akt and HER-2/neu are involved in the androgen receptor (AR) signaling pathway and whether they play a role in androgen-independent survival or growth of prostate cancer cells. METHODS: To investigated whether Akt is involved in the activation of AR pathway and plays a role in androgen-independent survival or growth of prostate cancer cells, we examine the effects of constitutively active Akt (CA-Akt) or dominant negative Akt (DN-Akt) on PSA transcriptional regulation, cell survival, and cell proliferation in the absence or presence of androgen. The in vivo and in vitro interaction between Akt and AR was detected by immunoprecipitation and pull-down assays. Immunocomplex kinase assays were used to determine whether AR is a substrate that can be phosphorylated by Akt. RESULTS: In the absence of androgen, CA-Akt stimulated PSA-luc reporter and DN-Akt inhibited the reporter. CA-Akt enhanced LNCaP cell survival in the absence of the hormone. The stimulatory effect of HER-2/neu on PSA transcription, cell survival and cell proliferation was dramatically reduced by DN-Akt or PI3K inhibitor LY294,002. AR is physically associated with Akt. The amino acid sequences of human AR reveals two conserved putative consensus Akt phosphorylation sites Ser-213 and Ser-791, both of them can phosphorylated by Akt. CONCLUSIONS: HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway.
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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 Molecular Pathology.