The importance of non-nuclear AR signaling in prostate cancer progression and therapeutic resistance

Zarif, Jelani C.; Miranti, Cindy K.

doi:10.1016/j.cellsig.2016.01.013

Cited by 46 publications

(54 citation statements)

References 158 publications

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“…AR is expressed in both basal and luminal cells of the prostatic epithelium where its primary role is to promote expression of genes involved in terminal differentiation, secretion and suppression of proliferation to maintain homeostasis [12,19,20,21,22,23,24]. …”

Section: The Androgen Receptor Pathwaymentioning

confidence: 99%

AR Signaling and the PI3K Pathway in Prostate Cancer

Crumbaker

Khoja

Joshua

2017

Cancers

130

119

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Prostate cancer is a leading cause of cancer-related death in men worldwide. Aberrant signaling in the androgen pathway is critical in the development and progression of prostate cancer. Despite ongoing reliance on androgen receptor (AR) signaling in castrate resistant disease, in addition to the development of potent androgen targeting drugs, patients invariably develop treatment resistance. Interactions between the AR and PI3K pathways may be a mechanism of treatment resistance and inhibitors of this pathway have been developed with variable success. Herein we outline the role of the PI3K pathway in prostate cancer and, in particular, its association with androgen receptor signaling in the pathogenesis and evolution of prostate cancer, as well as a review of the clinical utility of PI3K targeting.

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Section: The Androgen Receptor Pathwaymentioning

confidence: 99%

AR Signaling and the PI3K Pathway in Prostate Cancer

Crumbaker

Khoja

Joshua

2017

Cancers

130

119

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“…HoxB13 interacts with the DNA binding domain of AR (29), whereas C/EBPa did not show a strong AR domain selectivity for interaction, and its association with AR involved multiple AR domains (30). Relatively little is known about the structural basis for non-genomic interactions of AR and other nuclear receptors with signaling pathways involving MAPK, PI3K/Akt, PKC, PLC, and G-protein-coupled receptors (1). Notable exceptions include the direct or indirect associations of NRs with the Src homology 2 or 3 domains where proline-rich motifs in AR and the progesterone receptor or L XX L motifs in the estrogen receptor are required (54–57).…”

Section: Discussionmentioning

confidence: 99%

“…The androgen receptor (AR) 2 and other members of the nuclear receptor (NR) superfamily mediate the transcriptional activities of their ligands as well as some of their non-genomic actions (1–5). NRs in the cytosol, in the nucleus, or in association with plasma membrane proteins are known to interact with a variety of signaling pathway proteins, either as protein kinase substrates or as regulators of transcription or signal transduction.…”

Section: Introductionmentioning

confidence: 99%

The Amino-terminal Domain of the Androgen Receptor Co-opts Extracellular Signal-regulated Kinase (ERK) Docking Sites in ELK1 Protein to Induce Sustained Gene Activation That Supports Prostate Cancer Cell Growth

Rosati

Patki

Chari

et al. 2016

Journal of Biological Chemistry

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The ETS domain transcription factor ELK1 is in a repressive association with growth genes and is transiently activated through phosphorylation by ERK1/2. In prostate cancer (PCa) cells the androgen receptor (AR) is recruited by ELK1, via its amino-terminal domain (A/B), as a transcriptional co-activator, without ELK1 hyper-phosphorylation. Here we elucidate the structural basis of the interaction of AR with ELK1. The ELK1 polypeptide motifs required for co-activation by AR versus those required for activation of ELK1 by ERK were systematically mapped using a mammalian two-hybrid system and confirmed using a co-immunoprecipitation assay. The mapping precisely identified the two ERK-docking sites in ELK1, the D-box and the DEF (docking site for ERK, FXFP) motif, as the essential motifs for its cooperation with AR(A/B) or WTAR. In contrast, the transactivation domain in ELK1 was only required for activation by ERK. ELK1-mediated transcriptional activity of AR(A/B) was optimal in the absence of ELK1 binding partners, ERK1/2 and serum-response factor. Purified ELK1 and AR bound with a dissociation constant of 1.9 × 10−8 m. A purified mutant ELK1 in which the D-box and DEF motifs were disrupted did not bind AR. An ELK1 mutant with deletion of the D-box region had a dominant-negative effect on androgen-dependent growth of PCa cells that were insensitive to MEK inhibition. This novel mechanism in which a nuclear receptor impinges on a signaling pathway by co-opting protein kinase docking sites to constitutively activate growth genes could enable rational design of a new class of targeted drug interventions.

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“…[7,8]. Non-genomic AR signaling promotes tumor cell survival, proliferation, migration, invasion, and metastasis [9].…”

Section: Introductionmentioning

confidence: 99%

Nuclear loss and cytoplasmic expression of androgen receptor in penile carcinomas: role as a driver event and as a prognosis factor

et al. 2018

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Androgen receptor (AR) is a member of the steroid and nuclear family receptor that acts as transcription factor. AR signaling plays pivotal role in the development and progression of prostate cancer. However, the role of AR in penile cancer (PeCa) is poorly explored. Our previous molecular studies unveiled frequent AR mRNA loss in PeCa, which was further predicted as a major driver alteration in this neoplasm. Herein, we assessed the AR protein expression in 59 usual PeCa tissues and 42 surrounding normal tissues (SNT) by immunohistochemistry using a tissue microarray. In a paired analysis, we found a total absence of nuclear AR expression in PeCa while 95.2% of SNT samples presented strong nuclear AR expression (P < 0.001). Interestingly, 17 of 42 PeCa presented weak or moderate cytoplasmic AR staining, contrasting with 5 of 42 SNT (P = 0.008). Increased levels of AR cytoplasmic expression were related with poor prognosis features including advanced clinical staging (P = 0.044), compromised surgical margins (P = 0.005), and pathological inguinal node status (P = 0.047). Furthermore, AR cytoplasmic expression was also related with shorter overall survival (P = 0.032). In conclusion, the frequent loss of nuclear AR protein levels suggests a potential function in PeCa development. Based on this result, the androgen deprivation therapy is not indicated for PeCa patients. In addition, the AR cytoplasmic expression found in a significant number of cases (40.5%) showed prognostic value and pathways activated by the non-genomic AR signaling may represent a promising therapeutic strategy.

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The importance of non-nuclear AR signaling in prostate cancer progression and therapeutic resistance

Cited by 46 publications

References 158 publications

AR Signaling and the PI3K Pathway in Prostate Cancer

AR Signaling and the PI3K Pathway in Prostate Cancer

The Amino-terminal Domain of the Androgen Receptor Co-opts Extracellular Signal-regulated Kinase (ERK) Docking Sites in ELK1 Protein to Induce Sustained Gene Activation That Supports Prostate Cancer Cell Growth

Nuclear loss and cytoplasmic expression of androgen receptor in penile carcinomas: role as a driver event and as a prognosis factor

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