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Crosstalking between Androgen and PI3K/AKT Signaling Pathways in Prostate Cancer Cells

2014; Elsevier BV; Volume: 290; Issue: 5 Linguagem: Inglês

10.1074/jbc.m114.607846

1083-351X

Suk Hyung Lee, D. T. Johnson, Richard Luong, Zijie Sun,

Ubiquitin and proteasome pathways

Both androgen action and PI3K medicated signaling pathways have been implicated in prostate tumorigenesis. Our androgen receptor (AR) conditional transgenic mice developed murine prostatic intraepithelial neoplasia (mPIN) and prostatic adenocarcinoma lesions recapitulating human prostate cancer development and progression. Role of transgenic AR contributing to malignancy was demonstrated by high degree of transgenic AR expression in atypical and tumor cells in mPIN as well as prostatic adenocarcinoma lesions of the transgenic mice, but not in adjacent normal tissue. Interestingly, reduced PI3K/Akt activation also appeared in these mouse atypical and tumor cells, suggesting an interaction between androgen and PI3K/AKT pathways. In this study, we further investigated this interaction. We showed that the androgen depletion or knockdown of AR expression results in elevated levels of active phosphorylated AKT in prostate cancer cells. Castration of conditional Pten knock-out mice showed increased Akt, phosphorylated Akt, and pS6 expression in the mouse prostate. Using a series of newly generated Ar reporter and Pten knock-out compound mice, we showed that Pten loss directly represses endogenous Ar expression in prostatic epithelial cells. Moreover, Pten loss and PI3K/Akt activation reduced Ar-mediated transcription in purified Pten-null cells. This study provides novel evidence demonstrating interplay between androgen and PI3K pathways, as well as introduces unique and relevant mouse models for further studies of PI3K and AR pathways in the context of prostate tumorigenesis.Background: An interaction between androgen and PI3K/AKT pathways has been implicated in prostate cancer cells.Results: Conditional expression of AR transgene represses PI3K/Akt activation, and Pten loss results in reduced AR expression and transcriptional activity.Conclusion: Both androgen and PI3K/AKT pathways inversely regulate each other in prostate cancer cells.Significance: Interplay between androgen and PI3K/AKT pathways may directly contribute to prostate tumorigenesis. Both androgen action and PI3K medicated signaling pathways have been implicated in prostate tumorigenesis. Our androgen receptor (AR) conditional transgenic mice developed murine prostatic intraepithelial neoplasia (mPIN) and prostatic adenocarcinoma lesions recapitulating human prostate cancer development and progression. Role of transgenic AR contributing to malignancy was demonstrated by high degree of transgenic AR expression in atypical and tumor cells in mPIN as well as prostatic adenocarcinoma lesions of the transgenic mice, but not in adjacent normal tissue. Interestingly, reduced PI3K/Akt activation also appeared in these mouse atypical and tumor cells, suggesting an interaction between androgen and PI3K/AKT pathways. In this study, we further investigated this interaction. We showed that the androgen depletion or knockdown of AR expression results in elevated levels of active phosphorylated AKT in prostate cancer cells. Castration of conditional Pten knock-out mice showed increased Akt, phosphorylated Akt, and pS6 expression in the mouse prostate. Using a series of newly generated Ar reporter and Pten knock-out compound mice, we showed that Pten loss directly represses endogenous Ar expression in prostatic epithelial cells. Moreover, Pten loss and PI3K/Akt activation reduced Ar-mediated transcription in purified Pten-null cells. This study provides novel evidence demonstrating interplay between androgen and PI3K pathways, as well as introduces unique and relevant mouse models for further studies of PI3K and AR pathways in the context of prostate tumorigenesis. Background: An interaction between androgen and PI3K/AKT pathways has been implicated in prostate cancer cells. Results: Conditional expression of AR transgene represses PI3K/Akt activation, and Pten loss results in reduced AR expression and transcriptional activity. Conclusion: Both androgen and PI3K/AKT pathways inversely regulate each other in prostate cancer cells. Significance: Interplay between androgen and PI3K/AKT pathways may directly contribute to prostate tumorigenesis.