Androgen receptor phosphorylation: biological context and functional consequences

Koryakina, Yulia; Ta, Huy Q.; Gioeli, Daniel

doi:10.1530/erc-13-0472

Cited by 121 publications

(105 citation statements)

References 94 publications

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“…These posttranscriptional modifications (in combination with other modifications such as ubiquitination and methylation) act as an allosteric regulation fine-tune of receptor structure and function (Kumar & McEwan 2012, Koryakina et al 2014.…”

Section: :10mentioning

confidence: 99%

Androgen receptor signaling pathways as a target for breast cancer treatment

Pietri¹,

Conteduca²,

Andreis³

et al. 2016

Endocrine-Related Cancer

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The androgen receptor (AR) is a ligand-dependent transcription factor, and its effects on breast range from physiological pubertal development and age-related modifications to cancer onset and proliferation. The prevalence of AR in early breast cancer is around 60%, and AR is more frequently expressed in ER-positive than in ER-negative tumors. We offer an overview of AR signaling pathways in different breast cancer subtypes, providing evidence that its oncogenic role is likely to be different in distinct biological and clinical scenarios. In particular, in ER-positive breast cancer, AR signaling often antagonizes the growth stimulatory effect of ER signaling; in triple-negative breast cancer (TNBC), AR seems to drive tumor progression (at least in luminal AR subtype of TNBC with a gene expression profile mimicking luminal subtypes despite being negative to ER and enriched in AR expression); in HER2-positive breast cancer, in the absence of ER expression, AR signaling has a proliferative role. These data represent the rationale for AR-targeting treatment as a potentially new target therapy in breast cancer subset using androgen agonists in some AR-positive/ER-positive tumors, AR antagonists in triple-negative/ AR-positive tumors and in combination with anti-HER2 agents or with other signaling pathways inhibitors (including PI3K/MYC/ERK) in HER2-positive/AR-positive tumors. Only the ongoing and future prospective clinical trials will allow us to establish which agents are the best option in every specific condition, keeping in mind that there is evidence of opposite androgens and AR agonist/antagonist drug effects on cell proliferation particularly in AR-positive/ER-positive tumors.

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Section: :10mentioning

confidence: 99%

Androgen receptor signaling pathways as a target for breast cancer treatment

Pietri¹,

Conteduca²,

Andreis³

et al. 2016

Endocrine-Related Cancer

View full text Add to dashboard Cite

show abstract

“…This is in agreement with reports that cyclin-dependent kinases, viz., Cdk1 and Cdk9, phosphorylate AR Ser-81 and stabilize AR binding to chromatin [24, 25, 36]. Protein kinases play an important role in regulation of AR function and AR protein stability [37]. Protein kinases activated by growth factors (e.g., EGF and IGF-1) or cytokines (e.g., IL-6 and IL-8) are reported to activate AR in the absence of androgen [38], and several growth factor-stimulated protein kinases including Akt [39], Aurora A [40], Src [41], and cyclin-dependent kinases Cdk1 and Cdk9 [24, 25, 36] that phosphorylate AR depend either directly or indirectly on CaM for kinase activity.…”

Section: Discussionmentioning

confidence: 99%

Hydrazinobenzoylcurcumin inhibits androgen receptor activity and growth of castration-resistant prostate cancer in mice

Kim

Levin

et al. 2015

Oncotarget

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There is a critical need for therapeutic agents that can target the amino-terminal domain (NTD) of androgen receptor (AR) for the treatment of castration-resistant prostate cancer (CRPC). Calmodulin (CaM) binds to the AR NTD and regulates AR activity. We discovered that Hydrazinobenzoylcurcumin (HBC), which binds exclusively to CaM, inhibited AR activity. HBC abrogated AR interaction with CaM, suppressed phosphorylation of AR Serine81, and blocked the binding of AR to androgen-response elements. RNA-Seq analysis identified 57 androgen-regulated genes whose expression was significantly (p ≤ 0.002) altered in HBC treated cells as compared to controls. Oncomine analysis revealed that genes repressed by HBC are those that are usually overexpressed in prostate cancer (PCa) and genes stimulated by HBC are those that are often down-regulated in PCa, suggesting a reversing effect of HBC on androgen-regulated gene expression associated with PCa. Ingenuity Pathway Analysis revealed a role of HBC affected genes in cellular functions associated with proliferation and survival. HBC was readily absorbed into the systemic circulation and inhibited the growth of xenografted CRPC tumors in nude mice. These observations demonstrate that HBC inhibits AR activity by targeting the AR NTD and suggest potential usefulness of HBC for effective treatment of CRPC.

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“…However, an interesting question is how S6K1 regulates AR function. Accumulated evidence indicated the crucial role of S81 phosphorylation in AR nuclear translocation and transcriptional activation (Koryakina et al 2014). S81 phosphorylation also enhances AR protein stability, correlating with increased protein expression.…”

Section: :8mentioning

confidence: 99%

PYK2 via S6K1 regulates the function of androgen receptors and the growth of prostate cancer cells

Hsiao¹,

Huang²,

Hung³

et al. 2016

Endocrine-Related Cancer

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Androgen receptor (AR) is a steroid hormone receptor that functions as a transcription factor for regulating cell growth and survival. Aberrant AR function becomes a risk factor for promoting the progression of prostate cancer (PCa). In this study, we examined the roles of proline-rich tyrosine kinase 2 (PYK2) and ribosomal S6 kinase 1 (S6K1) in regulating AR expression and activity and growth properties in PCa cells. Compared with normal prostate tissues, PCa tumors exhibited high levels of PYK2 and S6K1 expression. Furthermore, the expression levels of PYK2 and S6K1 were significantly correlated with nuclear AR expression in PCa tissues. We further found the association between PYK2, S6K1, and AR in their protein expression and phosphorylation levels among normal prostate PZ-HPV-7 cells and prostate cancer LNCaP and 22Rv1 cells. Overexpression of the wild-type PYK2 in PZ-HPV-7 and LNCaP cells promoted AR and S6K1 expression and phosphorylation as well as enhanced cell growth. In contrast, expression of the mutated PYK2 or knockdown of PYK2 expression in LNCaP or 22Rv1 cells caused reduced expression or phosphorylation of AR and S6K1 as well as retarded cell growth. Under an androgen-deprived condition, PYK2-promoted AR expression and phosphorylation and PSA production in LNCaP cells can be abolished by knocking down S6K1 expression. In summary, our data suggested that PYK2 via S6K1 activation modulated AR function and growth properties in PCa cells. Thus, PYK2 and S6K1 may potentially serve as therapeutic targets for PCa treatment.

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Androgen receptor phosphorylation: biological context and functional consequences

Cited by 121 publications

References 94 publications

Androgen receptor signaling pathways as a target for breast cancer treatment

Androgen receptor signaling pathways as a target for breast cancer treatment

Hydrazinobenzoylcurcumin inhibits androgen receptor activity and growth of castration-resistant prostate cancer in mice

PYK2 via S6K1 regulates the function of androgen receptors and the growth of prostate cancer cells

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