5α-androstane-3α,17β-diol selectively activates the canonical PI3K-AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signalingReportar como inadecuado




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Genomic Medicine

, Volume 1, Issue 3–4, pp 139–146

First Online: 27 February 2008Received: 29 November 2007Accepted: 14 February 2008DOI: 10.1007-s11568-008-9018-9

Cite this article as: Dozmorov, M.G., Yang, Q., Matwalli, A. et al. HUGO J 2007 1: 139. doi:10.1007-s11568-008-9018-9

Abstract

5α-Androstane-3α,17β-diol 3α-diol is reduced from the potent androgen, 5α-dihydrotestosterone 5α-DHT, by reductive 3α-hydroxysteroid dehydrogenases 3α-HSDs in the prostate. 3α-diol is recognized as a weak androgen with low affinity toward the androgen receptor AR, but can be oxidized back to 5α-DHT. However, 3α-diol may have potent effects by activating cytoplasmic signaling pathways, stimulating AR-independent prostate cell growth, and, more importantly, providing a key signal for androgen-independent prostate cancer progression. A cancer-specific, cDNA-based membrane array was used to determine 3α-diol-activated pathways in regulating prostate cancer cell survival and-or proliferation. Several canonical pathways appeared to be affected by 3α-diol-regulated responses in LNCaP cells; among them are apoptosis signaling, PI3K-AKT signaling, and death receptor signaling pathways. Biological analysis confirmed that 3α-diol stimulates AKT activation; and the AKT pathway can be activated independent of the classical AR signaling. These observations sustained our previous observations that 3α-diol continues to support prostate cell survival and proliferation regardless the status of the AR. We provided the first systems biology approach to demonstrate that 3α-diol-activated cytoplasmic signaling pathways are important components of androgen-activated biological functions in human prostate cells. Based on the observations that levels of reductive 3α-HSD expression are significantly elevated in localized and advanced prostate cancer, 3α-diol may, therefore, play a critical role for the transition from androgen-dependent to androgen-independent prostate cancer in the presence of androgen deprivation.

KeywordsAndrogen receptor Cell proliferation Gene expression Microarray PI3K-AKT pathway Prostate cancer Abbreviations3α-diol5α-Androstane-3α, 17α-diol

3α-HSD3α-Hydroxysteroid dehydrogenase

5α-DHT5α-Dihydrotestosterone

ARAndrogen receptor

ARGAndrogen responsive gene

BNTBelow noise threshold

FBSFetal bovine serum

GEOGene expression omnibus

Electronic supplementary materialThe online version of this article doi:10.1007-s11568-008-9018-9 contains supplementary material, which is available to authorized users.

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Autor: Mikhail G. Dozmorov - Qing Yang - Adam Matwalli - Robert E. Hurst - Daniel J. Culkin - Bradley P. Kropp - Hsueh-Kung Li

Fuente: https://link.springer.com/



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