Stabilization of androgen receptor protein is induced by agonist, not by antagonists

Furutani, Takashi; Watanabe, Tomoyuki; Tanimoto, Kyouko; Hashimoto, Takamichi; Koutoku, Hiroshi; Kudoh, Masafumi; Shimizu, Yoshiyuki; Kato, Shigeaki; Shikama, Hisataka

doi:10.1016/s0006-291x(02)00564-8

Cited by 36 publications

(33 citation statements)

References 29 publications

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“…The FOXO3a-AR interaction was androgen dependent in both cytoplasmic and nuclear extracts. In both Figures 5a and b, the level of cytoplasmic AR is increased in cells treated with androgen, consistent with reports that ligand stabilizes AR levels (Furutani et al, 2002;Li et al, 2003).…”

Section: Foxo3a Binds the Arsupporting

confidence: 90%

FOXO3a mediates the androgen-dependent regulation of FLIP and contributes to TRAIL-induced apoptosis of LNCaP cells

et al. 2008

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Androgen-withdrawal-induced apoptosis (AWIA) is deregulated in androgen refractory prostate cancer. Androgens have been shown to positively regulate expression of the antiapoptotic FADD-like interleukin-1b-converting enzyme (FLICE)-like inhibitory protein (FLIP), and reduced FLIP expression precedes apoptosis after androgen withdrawal. Here, we show that FLIP protein expression is downregulated in castrated rats, while in LNCaP cells, androgens regulate FLIP in a manner that is dependent on phosphoinositol-3-kinase (PI3K) and Akt signaling. Specifically, treatment of LNCaP cells with LY294002, or expression of either PTEN or a nonphosphorylatable form of FOXO3a (FOXO3aTM), downregulates FLIP protein and mRNA. Conversely, treatment with androgens in the absence of PI3/Akt signaling, or following expression of FOXO3aTM, leads to increased FLIP expression. A FOXO3a binding site was identified in the FLIP promoter and shown necessary for the combined effects of androgens and FOXO3a on FLIP transcription. FOXO3a binds the androgen receptor, suggesting that the transcriptional synergy depends on an interaction between these proteins. Finally, LNCaP cells are sensitized to TRAIL-induced apoptosis by PTEN or LY294002, and rescued by androgens. FOXO3aTM also sensitizes cells to androgen-inhibited TRAIL apoptosis. Androgen rescue was diminished when either FOXO3a or FLIP was reduced by siRNA. These data support a role for FOXO3a in AWIA.

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Section: Foxo3a Binds the Arsupporting

confidence: 90%

FOXO3a mediates the androgen-dependent regulation of FLIP and contributes to TRAIL-induced apoptosis of LNCaP cells

et al. 2008

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“…DIMN reduced PSA protein levels more effectively than the AR antagonists BIC and OHF at the same concentration (10 M). Interestingly, DIMN also reduced the protein level of the AR, as previously reported with BIC and OHF (53,63,64). Taken together, these results suggest that the compound DIMN inhibits AR function in prostate cancer cells and inhibit the expression of endogenous AR target genes in a similar fashion to the conventional AR antagonists, BIC and OHF.…”

Section: Suppression Of Androgen-induced Ar Target Gene Expression Bysupporting

confidence: 84%

Structure-based Virtual Screening and Identification of a Novel Androgen Receptor Antagonist

Song

Yang

Park

et al. 2012

Journal of Biological Chemistry

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Background:The androgen receptor (AR) is the primary drug target for prostate cancer treatment. Results: We have identified a novel AR antagonist, the compound 6-(3,4-dihydro-1H-isoquinolin-2-yl)-N-(6-methylpyridin-2-yl)nicotinamide (DIMN) that inhibits the growth of AR-positive prostate cancer cells. Conclusion: DIMN has been identified as a new lead structure targeting the AR. Significance: This novel AR antagonist could be a useful therapeutic agent for prostate cancer treatment.

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“…DHT and flutamide compete for AR binding and, when bound by DHT, AR undergoes conformational changes that stabilize it and allow the recruitment of transcriptional coactivators (Furutani et al, 2002). Flutamide antagonizes AR activity by abrogating its stabilization, leading to degradation, and by preventing transactivation (Furutani et al, 2002).…”

Section: Transcription Of Fgfr2-iiib and Fgf10 Requires Ar Activitymentioning

confidence: 99%

Development of the mammalian urethra is controlled by Fgfr2-IIIb

et al. 2005

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Stabilization of androgen receptor protein is induced by agonist, not by antagonists

Cited by 36 publications

References 29 publications

FOXO3a mediates the androgen-dependent regulation of FLIP and contributes to TRAIL-induced apoptosis of LNCaP cells

FOXO3a mediates the androgen-dependent regulation of FLIP and contributes to TRAIL-induced apoptosis of LNCaP cells

Structure-based Virtual Screening and Identification of a Novel Androgen Receptor Antagonist

Development of the mammalian urethra is controlled by Fgfr2-IIIb

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