Abstract
Progression to castration resistance is a major problem in the treatment of advanced prostate cancer and is likely to be driven by activation of several molecular pathways, including androgen receptor (AR) and cyclic AMP-dependent protein kinase A (PKA). In this study, we examined the therapeutic efficacy of a combined inhibition of the AR and the regulatory subunit type Iα (RIα) of protein kinase A with second generation antisense oligonucleotides (ODNs) in androgen-sensitive LNCaP and castration-resistant LNCaPabl tumors in vivo. We found that targeting the AR alone inhibited LNCaP, as well as LNCaPabl tumors. Combined inhibition resulted in an improved response over single targeting and even a complete tumor remission in LNCaPabl. Western blot analysis revealed that both ODNs were effective in reducing their target proteins when administered alone or in combination. In addition, treatment with the ODNs was associated with an induction of apoptosis. Our data suggest that dual targeting of the AR and PKARIα is more effective in inhibiting LNCaP and LNCaPabl tumor growth than single treatment and may give a treatment benefit, especially in castration-resistant prostate cancers.
Highlights
Androgen receptor (AR) activation classically acts through binding of androgens, which regulate normal prostate development and function
androgen receptor (AR) and PKARIα are implicated in the activation of AR signaling and progression of prostate cancer towards castration resistance
While there is evidence that single targeting of either AR [16,17,18,19,20,21] or PKARIα [29,49] has tumor-inhibitory potential, the data presented in this study are the first showing the effects of combined targeting of these two molecules in prostate cancer in vivo
Summary
Androgen receptor (AR) activation classically acts through binding of androgens, which regulate normal prostate development and function. There are five fundamental and non-mutually exclusive mechanisms known, which are thought to mediate aberrant AR activation in castration-resistant prostate cancer (CRPC) (recently reviewed by [1] and [2]) These include low levels of androgens remaining in the tumor tissue despite hormone ablation, which may in part result from in situ steroidogenesis [3], mutations in the AR gene, broadening the ligand binding spectrum of the receptor [4,5,6], AR overexpression [7], altered expression of co-regulatory molecules [8] and, crosstalk with other intracellular signaling pathways [9,10,11]. With regard to therapy, one major question is how aberrant
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