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Abstract
Progression to androgen independence is the lethal end stage of prostate cancer. We used expression of androgen receptor (AR)-targeted short hairpin RNAs (shRNA) to directly test the requirement for AR in ligand-independent activation of androgen-regulated genes and hormone-independent tumor progression. Transient transfection of LNCaP human prostate cancer cells showed that AR shRNA decreased R1881 induction of the prostate-specific antigen (PSA)-luciferase reporter by 96%, whereas activation by forskolin, interleukin-6, or epidermal growth factor was inhibited 48% to 75%. Whereas the antiandrogen bicalutamide provided no further suppression, treatment with the mitogen-activated protein kinase (MAPK) inhibitor U0126 completely abrogated the residual activity, indicating a MAPK-dependent, AR-independent pathway for regulating the PSA promoter. Expression of doxycycline-inducible AR shRNA expression in LNCaP cells resulted in decreased levels of AR and PSA as well as reduced proliferation in vitro. When these cells were grown as xenografts in immunocompromised mice, induction of AR shRNA decreased serum PSA to below castration nadir levels and significantly retarded tumor growth over the entire 55-day experimental period. This is the first demonstration that, by inducibly suppressing AR expression in vivo, there is an extensive delay in progression to androgen independence as well as a dramatic inhibition of tumor growth and decrease in serum PSA, which exceeds that seen with castration alone. Based on these findings, we propose that suppressing AR expression may provide superior therapeutic benefit in reducing tumor growth rate than castration and may additionally be very effective in delaying progression to androgen independence.
Highlights
Prostate cancer is the most commonly diagnosed nonskin cancer in males and one of the leading causes of cancer deaths in men [1]
Using LNCaP cells transfected with short hairpin RNAs (shRNA), we show for the first time that knockdown of androgen receptor (AR) inhibited most, but not all, activation of the prostate-specific antigen (PSA) promoter by nonandrogenic compounds and that suppressing AR expression was far more effective than castration in blocking tumor growth and decreasing serum PSA levels in LNCaP xenografts
The AR seems to play a pivotal role in hormone-refractory prostate cancer [36], and gene expression profiles have shown that the AR is the only gene that is consistently up-regulated when prostate xenograft tumors become androgen independent [37]
Summary
Prostate cancer is the most commonly diagnosed nonskin cancer in males and one of the leading causes of cancer deaths in men [1]. The effects of androgen withdrawal therapy are temporary due to progression of surviving. EGF levels are elevated in prostate cancer patients, but the effect on AR transcriptional activity continues to be debated [15, 16]. Forskolinmediated increased intracellular cyclic AMP levels have been reported to activate AR in the absence of androgen presumably through cross-talk between the protein kinase A and AR pathways [17]. It is unresolved whether a functional AR is required for ligand-independent activation of androgen target genes, such as prostate-specific antigen (PSA)
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