Cell-cycle-dependent regulation of androgen receptor function

Koryakina, Yulia; Knudsen, Karen E.; Gioeli, Daniel

doi:10.1530/erc-14-0549

Cited by 30 publications

(31 citation statements)

References 48 publications

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“…However, the interphase activation of Aurora would be expected to be PC-1-independent. AR function is cell cycle-dependent, and S308 phosphorylation by Cdk1 regulates its localization and transcriptional activity (46). Additionally, phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death (30).…”

Section: Discussionmentioning

confidence: 99%

Aurora Kinase A Promotes AR Degradation via the E3 Ligase CHIP

Sarkar

Brautigan

Larner

2017

Molecular Cancer Research

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Reducing the levels of the androgen receptor (AR) is one of the most viable approaches to combat castration-resistant prostate cancer (CRPC). Previously, we observed that proteasomal-dependent degradation of AR in response to 2-methoxyestradiol (2-ME) depends primarily on the E3 ligase C-terminus of HSP70-interacting protein (STUB1/CHIP). Here, 2-ME stimulation activates CHIP by phosphorylation via Aurora kinase A (AURKA). Aurora A kinase inhibitors and RNAi knockdown of Aurora A transcript selectively blocked CHIP phosphorylation and AR degradation. Aurora A kinase is activated by 2-ME in S-phase as well as during mitosis, and phosphorylates CHIP at S273. Prostate cancer cells expressing a S273A mutant of CHIP have attenuated AR degradation upon 2-ME treatment compared to cells expressing wild-type CHIP, supporting the idea that CHIP phosphorylation by Aurora A activates its E3 ligase activity for the AR. These results reveal a novel 2-ME→Aurora A→CHIP→AR pathway which promotes AR degradation via the proteasome, that may offer novel therapeutic opportunities for prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Aurora Kinase A Promotes AR Degradation via the E3 Ligase CHIP

Sarkar

Brautigan

Larner

2017

Molecular Cancer Research

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“…CDK1 activity promotes AR S81 phosphorylation and protein stabilization, thereby increasing AR activity (41). Recently, we reported that CDK1 phosphorylates AR on S308, and that this phosphorylation may regulate AR localization during mitosis (42). CDK1 activity increases as PCa progresses (29,43).…”

Section: Discussionmentioning

confidence: 99%

Checkpoint Kinase 2 Negatively Regulates Androgen Sensitivity and Prostate Cancer Cell Growth

Ivey

Frierson

et al. 2015

Cancer Research

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Prostate cancer (PCa) is the second leading cause of cancer death in American men, and curing metastatic disease remains a significant challenge. Nearly all patients with disseminated PCa initially respond to androgen deprivation therapy (ADT), but virtually all patient will relapse and develop incurable castration-resistant prostate cancer (CRPC). A high-throughput RNAi screen to identify signaling pathways regulating PCa cell growth led to our discovery that Checkpoint Kinase 2 (CHK2) knockdown dramatically increased PCa growth and hypersensitized cells to low androgen levels. Mechanistic investigations revealed that the effects of CHK2 were dependent on the downstream signaling proteins CDC25C and CDK1. Moreover, CHK2 depletion increased androgen receptor (AR) transcriptional activity on androgen-regulated genes, substantiating the finding that CHK2 affects PCa proliferation, partly, through the AR. Remarkably, we further show that CHK2 is a novel AR-repressed gene, suggestive of a negative feedback loop between CHK2 and AR. Additionally, we provide evidence that CHK2 physically associates with the AR, and that cell cycle inhibition increased this association. Finally, immunohistochemical analysis of CHK2 in prostate cancer patient samples demonstrated a decrease in CHK2 expression in high-grade tumors. In conclusion, we propose that CHK2 is a negative regulator of androgen sensitivity and PCa growth, and that CHK2 signaling is lost during prostate cancer progression to castration resistance. Thus, perturbing CHK2 signaling may offer a new therapeutic approach for sensitizing CRPC to ADT and radiation.

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“…Cell cycle progression is driven by the rising and falling in levels of cyclins and cyclin dependent kinase (CDKs), in addition to the activation of these proteins 103 . In prostate cancer, AR is regulated in a cell-cycle-dependent manner 104 . Nuclear transactivation of AR is highest in G1 and decreases in S phase, while the same changes occur in AR phosphorylation and cellular localization 104 .…”

Section: Cell Cycle Regulation Prostate Cancermentioning

confidence: 99%

“…In prostate cancer, AR is regulated in a cell-cycle-dependent manner 104 . Nuclear transactivation of AR is highest in G1 and decreases in S phase, while the same changes occur in AR phosphorylation and cellular localization 104 . Further, CDK1 has been shown to phosphorylate AR on S308 in response to ligand binding 104 .…”

Section: Cell Cycle Regulation Prostate Cancermentioning

confidence: 99%

ARe we there yet? Understanding androgen receptor signaling in breast cancer

et al. 2020

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The role of androgen receptor (AR) activation and expression is well understood in prostate cancer. In breast cancer, expression and activation of AR is increasingly recognized for its role in cancer development and its importance in promoting cell growth in the presence or absence of estrogen. As both prostate and breast cancers often share a reliance on nuclear hormone signaling, there is increasing appreciation of the overlap between activated cellular pathways in these cancers in response to androgen signaling. Targeting of the androgen receptor as a monotherapy or in combination with other conventional therapies has proven to be an effective clinical strategy for the treatment of patients with prostate cancer, and these therapeutic strategies are increasingly being investigated in breast cancer. This overlap suggests that targeting androgens and AR signaling in other cancer types may also be effective. This manuscript will review the role of AR in various cellular processes that promote tumorigenesis and metastasis, first in prostate cancer and then in breast cancer, as well as discuss ongoing efforts to target AR for the more effective treatment and prevention of cancer, especially breast cancer.

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Cell-cycle-dependent regulation of androgen receptor function

Cited by 30 publications

References 48 publications

Aurora Kinase A Promotes AR Degradation via the E3 Ligase CHIP

Aurora Kinase A Promotes AR Degradation via the E3 Ligase CHIP

Checkpoint Kinase 2 Negatively Regulates Androgen Sensitivity and Prostate Cancer Cell Growth

ARe we there yet? Understanding androgen receptor signaling in breast cancer

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