BERKELEY, CA (UroToday.com) - The standard therapy for localized and advanced prostate cancer (PCa) is androgen deprivation therapy (ADT) in the form of medical or surgical castration. Although ADT leads to the initial regression of tumors, the recurrence of more aggressive castration-resistant PCa (CRPC) is inevitable. CRPC exhibits the nature of heterogeneity and complexity; this suggests that multiple cellular pathways may cooperatively promote progression of CRPC and render the tumors insensitive to therapy. Identification and validation of novel targets may assist the development of novel therapies.
The emerging evidence suggests that cyclic adenosine monophosphate (cAMP) activated protein kinase A (PKA) pathway may contribute to the progression of CRPC.[1] PKA is a serine/threonine kinase and is dependent on cAMP for its activity.[2] The cAMP is a second messenger and plays a role in metabolism, cellular growth, differentiation, gene expression, and apoptosis.[2] The family of cyclic nucleotide phosphodiesterase isozymes (PDEs) regulates intracellular levels of cAMP and cGMP. The cAMP-specific PDEs, including PDE4, PDE7 and PDE8 family of proteins, play important roles in controlling the activity of the PKA pathway.[1] PDE4 family of proteins is mainly expressed in inflammatory cells, brain, endothelial cells, and cardiovascular tissues. PKA in turn mediates the activities of the PDEs. Thus, there is a reciprocal regulation between PDEs and PKA pathways.[1]
The aim of a recent reported study by Sarwar, et al., published in Urologic Oncology.[3] is to investigate whether cAMP/PKA may be responsible for the activation of AR/PSA signaling during the progression of CRPC in the absence of androgen. Sarwar et al., showed that metastatic lesions from PCa patients had significantly higher levels of AR and R2β (PRKAR2B) mRNA expression compared with the primary PCa specimens or normal prostate tissues. In contrast, expression of R1α (PRKAR1A) and PDE4B was significantly lower in metastatic specimens and was reversely correlated with AR. These results suggest that (cAMP) activated PKA pathway may be of clinical importance in PCa.
Sarwar, et al., showed that inhibition of PDE4 using rolipram increased AR and PSA expression in LNCaP cells. The effect of rolipram on AR was equivalent to what was achieved by using androgen. Forskolin treatment led to an increase in PSA level, but not AR in LNCaP cells. This study suggests that cAMP/PKA pathways may cross-talk with AR to enhance the expression of PSA.
Sarwar, et al., showed constitutive activation of cAMP/PKA pathway by forskolin-induced features of neuroendocrine differentiation in LNCaP cells. PCa cells can differentiate into neuroendocrine cells, which are androgen-independent. In androgen-insensitive PC3 cells, cAMP-dependent pathways mediate MMP9 expression. These data suggest that cAMP/PKA pathway may promote adoption of PCa cells to a more aggressive phenotype, in the absence of hormones.
The novel findings by Sarwar, et al., suggest that deregulation of multiple signal transduction pathways and their correlation with AR in prostate cancer cells may reflect the complexity of PCa progression and metastasis. This study provides novel information and raised the possibility for future studies to investigate the different aspects of signaling pathways.
References:
- Sarwar M, Persson JL. The Protein Kinase A (PKA) Intracellular Pathway and Androgen Receptor: A Novel Mechanisms Underlying the Castration-resistant and Metastatic Prostate Cancer. J Cancer Sci Ther 2011, S5http://dx.doi.org/10.4172/1948-5956.S5-003
- Sakamoto KM, Frank DA. CREB in the pathophysiology of cancer: implications for targeting transcription factors for cancer therapy. Clin Cancer Res 2009;15:2583-7.
- Sarwar M, Sandberg S, Abrahamsson PA, Persson JL. Protein kinase A (PKA) pathway is functionally linked to androgen receptor (AR) in the progression of prostate cancer. Urol Oncol. 2013 Feb 12. pii: S1078-1439(12)00315-8.
Written by:
Jenny L. Persson, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Experimental Cancer Research, Clinical Research Center, Lund University Sweden, 205 02 Malmö, Sweden
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