The Protein Kinase A (PKA) Intracellular Pathway and Androgen Receptor: A Novel Mechanism Underlying the Castration-resistant and Metastatic Prostate Cancer

Androgen signaling via the androgen receptor (AR) is involved in normal prostate development and prostate cancer progression. In addition to androgen binding, a variety of protein kinases, including cyclic AMP-dependent protein kinase A (PKA), can activate the AR. Although hormone deprivation, especially that of androgen, continues to be an important strategy for treating prostate cancer patients, the disease ultimately progresses to castration-resistant prostate cancer (CRPC), despite a continuous hormone-deprived environment. To date, it remains unclear which pathways in this progression are active and targetable. Here, we performed a proteomic analysis of VCaP cells stimulated with androgen or forskolin to identify proteins specific for androgen-induced and androgen-bypassing signaling, respectively. Patterns of differentially expressed proteins were quantified, and eight proteins showing significant changes in expression were identified. Functional information, including a Gene Ontology analysis, revealed that most of these proteins are involved in metabolic processes and are associated with cancer. The mRNA and protein expression of selected proteins was validated, and functional correlations of identified proteins with signaling in VCaP cells were assessed by measuring metabolites related to each enzyme. These analyses offered new clues regarding effector molecules involved in prostate cancer development, insights that are supported by the demonstration of increased expression levels of the eight identified proteins in prostate cancer patients and assessments of the progression-free interval. Taken together, our findings show that aberrant levels of eight proteins reflect molecular changes that are significantly regulated by androgen and/or PKA signaling pathways, suggesting possible molecular mechanisms of CRPC.

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The role of protein kinase A pathway and cAMP responsive element-binding protein in androgen receptor-mediated transcription at the prostate-specific antigen locus

Journal of Molecular Endocrinology ◽

10.1677/jme.1.01701 ◽

2005 ◽

Vol 34 (1) ◽

pp. 107-118 ◽

Cited By ~ 40

Author(s):

J Kim ◽

L Jia ◽

M R Stallcup ◽

G A Coetzee

Keyword(s):

Prostate Cancer ◽

Signal Transduction ◽

Androgen Receptor ◽

Protein Kinase ◽

Specific Antigen ◽

Element Binding Protein ◽

Responsive Element ◽

Camp Responsive Element Binding ◽

Kinase A ◽

Androgen Independent

Androgen-independent prostate cancer is a lethal form of the disease that is marked by metastasis and rapid proliferation in its final stages. As no effective therapy for this aggressive tumor currently exists, it is imperative to elucidate and target the mechanisms involved in the progression to androgen independence. Accumulating evidence indicates that aberrant activation of androgen receptor (AR) via signal transduction pathways, AR gene mutation and/or amplification, and/or coregulator alterations may contribute to the progression of prostate cancer. In the present study, the effects of protein kinase A (PKA) signaling and its downstream factors on AR activity at the prostate-specific antigen (PSA) gene were tested. Activation of PKA by forskolin resulted in enhanced androgen-induced expression of the PSA gene, an effect that was blocked by the AR antagonist, bicalutamide. Interestingly, when either p300 or CBP was overexpressed, PKA activation was sufficient to stimulate PSA promoter-driven transcription in the absence of androgen, which was not inhibited by bicalutamide. PKA activation did not significantly alter AR protein levels but significantly increased the phosphorylated form of its downstream effector, cAMP responsive element-binding protein (CREB) in the presence of androgen. Furthermore, chromatin immunoprecipitation showed that the combination of androgen and forskolin increased phosphorylated CREB occupancy, which was accompanied by histone acetylation, at the putative cAMP responsive element located in the 5′ upstream regulatory region of the PSA gene. Remarkably, mammalian two-hybrid assay indicated that p300/CBP may bridge the interaction between AR and CREB, suggesting a novel enhanceosomal cooperation. These results demonstrate an intriguing interplay between a signal transduction pathway, coactivator overexpression and AR signaling as a possible combined mechanism of progression to androgen-independent prostate cancer.

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Androgen-independent Induction of Prostate-specific Antigen Gene Expression via Cross-talk between the Androgen Receptor and Protein Kinase A Signal Transduction Pathways

Journal of Biological Chemistry ◽

10.1074/jbc.274.12.7777 ◽

1999 ◽

Vol 274 (12) ◽

pp. 7777-7783 ◽

Cited By ~ 191

Author(s):

Marianne D. Sadar

Keyword(s):

Gene Expression ◽

Signal Transduction ◽

Androgen Receptor ◽

Protein Kinase ◽

Protein Kinase A ◽

Prostate Specific Antigen ◽

Specific Antigen ◽

Signal Transduction Pathways ◽

Kinase A ◽

Androgen Independent

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Androgen receptor antagonists for prostate cancer therapy

Endocrine Related Cancer ◽

10.1530/erc-13-0545 ◽

2014 ◽

Vol 21 (4) ◽

pp. T105-T118 ◽

Cited By ~ 55

Author(s):

Christine Helsen ◽

Thomas Van den Broeck ◽

Arnout Voet ◽

Stefan Prekovic ◽

Hendrik Van Poppel ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Practice ◽

Androgen Receptor ◽

Metastatic Prostate Cancer ◽

Castration Resistant ◽

Androgen Action ◽

Conflicting Evidence ◽

Prostate Cancer Therapy ◽

Androgen Receptor Antagonists

Androgen deprivation is the mainstay therapy for metastatic prostate cancer (PCa). Another way of suppressing androgen receptor (AR) signaling is via AR antagonists or antiandrogens. Despite being frequently prescribed in clinical practice, there is conflicting evidence concerning the role of AR antagonists in the management of PCa. In the castration-resistant settings of PCa, docetaxel has been the only treatment option for decades. With recent evidence that castration-resistant PCa is far from AR-independent, there has been an increasing interest in developing new AR antagonists. This review gives a concise overview of the clinically available antiandrogens and the experimental AR antagonists that tackle androgen action with a different approach.

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