Enhanced antiproliferative and proapoptotic effects on prostate cancer cells by simultaneously inhibiting androgen receptor and cAMP‐dependent protein kinase A

Abstract

The androgen-signaling pathway with the androgen receptor (AR) as its key molecule is widely understood to influence prostate tumor growth significantly even after androgen ablation. Under androgen-deprived conditions, the AR may be activated inappropriately through interaction with other molecules, including cyclic AMP-dependent protein kinase A (PKA). In a previous study, we have shown that knocking down the AR significantly inhibits prostate tumor growth. In this study, we show that combined inhibition of the AR and the regulatory subunit I alpha of PKA (RIa) with small interference RNAs significantly increased the growth-inhibitory and proapoptotic effects of AR knockdown. This treatment strategy was effective in androgen-sensitive and in androgen ablation-resistant prostate cancer cells. In addition, we report that downregulating PKA RIa was sufficient to inhibit PKA signaling and interestingly also impaired AR expression and activation. Vice versa, AR knockdown induced a decline in PKA RIa, associated with reduced PKA activity. This mutual influence on expression level was specific, because siRNAs against the AR did not affect expression of PKA RIa in AR negative DU-145 cells and a siRNA control did not affect protein expression. Another important finding of our study was that depletion of PKA RIa also potentiated the antiproliferative effect of the antiandrogen bicalutamide in androgen-sensitive LNCaP. We therefore concluded that combined inhibition of PKA RIa and AR may be a promising new therapeutic option for prostate cancer patients and might be superior to solely preventing AR expression.

The evaluation of involvement of angiotensin II, its receptors, and androgen receptor in endometrial cancer

“…AR signalling in case of prostate cancer can be inhibited by short hairpin RNA (shRNA) that results in weakened ligand-independent activation that leads to delayed tumor progression. The knockdown of AR results in decreased tumor growth [51,52]. The other approach to inhibit AR activity was the usage of small-molecule antagonist of AR that blocks protein-protein interactions important for AR transcriptional activity [53].…”

Phosphodiesterase sequence variants may predispose to prostate cancer

“…It was discovered that the use of Rolipram®, a selective PDE4 inhibitor, enhances the production of cAMP/PKA and increases AR and PSA expression significantly (Sarwar et al 2014). Prostatic tissue is indeed highly sensitive to cAMP (Faucz et al 2011), and both PKA activity and cAMP levels have been associated with PCa (Chung, et al 2009; Desiniotis, et al 2010; Dimitriadis, et al 2008; Sarwar et al 2014). Our finding in this study that a novel, somatic nonsynonymous PDE4B variant (p.Asn38Lys) is present in PCa patients, may explain the down-regulation of PDE4B in PCa that has been described by others (Kashiwagi et al 2012).…”

“…In addition, higher intracellular levels of cGMP have been reported to “crossover” and activate this kinase (Cornwell, et al 1994; Hood and Granger 1998). Over-expression of PKA has already been associated with PCa (Desiniotis et al 2010; Merkle and Hoffmann 2011), and other types of cancers (Almeida, et al 2012; Horvath, et al 2010; Horvath, et al 2008; Horvath, et al 2006a; Libe et al 2011; Stratakis, et al 2010). …”

Mechanistic rationale for MCL1 inhibition during androgen deprivation therapy

“…For downregulation of CDC20, FBXW7 and HUWE1 ON-TARGET plus smart pools consisting of four specific siRNA sequences and non-targeting control ON-TARGET plus smart pool (Dharmacon, ThermoScientific) were used and cells were transfected at a concentration of 50 nM. AR was downregulated by transfection of 30 nM with the following annealed constructs: sense 5′-GCACUGCUACUCUUCAGCAdTdT-3′ and antisense 5′-UGCUGAAGAGUAGCAGUGCdTdT-3′, as previously described [44]. …”