Abstract
The inappropriate activation of androgen receptor (AR) by nonsteroids is considered a potential mechanism in the emergence of hormone-refractory prostate tumors, but little is known about the properties of these "pseudoactivated" AR. Here, we present the first comprehensive analysis closely examining the properties of AR activated by the neuropeptide bombesin that distinguish it from androgen-activated AR. We show that bombesin-activated AR (a) is required for bombesin-induced growth of LNCaP cells, (b) has a transcriptional profile overlapping with, but not identical to, androgen-activated AR, (c) activates prostate-specific antigen by preferentially binding to its proximal promoter, and (d) assembles a distinct coactivator complex. Significantly, we found that Src kinase is critical for bombesin-induced AR-mediated activity and is required for translocation and transactivation of AR. Additionally, we identify c-Myc, a Src target gene, to be activated by bombesin and a potential coactivator of AR-mediated activity specific to bombesin-induced signaling. Because Src kinase is often activated by other nonsteroids, such as other neuropeptides, growth factors, chemokines, and cytokines, our findings have general applicability and provide rationale for investigating the efficacy of the Src kinase pathway as a target for the prevention of relapsed prostate cancers.
Highlights
Prostate cancer is the most common noncutaneous malignant transformation in American men
We can show that LNCaP cells respond to bombesin at a wide range of concentrations, we have used the upper range in our signaling studies, as others have done [23, 24], to account for the effect of neutral endopeptidase expressed at the surface of LNCaP cells, which cleaves and inactivates neuropeptides [25]
Our data show that bombesin-induced androgen receptor (AR) activation proceeds via a mechanism that incorporates components used by conventional DHT-induced signaling and a novel, distinctive pathway dependent on G protein–coupled receptor (GPCR)-Src cross-talk, which has corresponding effects on the assembly of AR transcriptional complexes and gene expression patterns
Summary
Prostate cancer is the most common noncutaneous malignant transformation in American men. The initial emergence of prostate cancer is typically androgen dependent, treatable with androgen ablation therapy. In the majority of cases, tumors reemerge as androgen independent and highly aggressive and are associated with most prostate cancer–related deaths. Androgen is suppressed under androgen ablation therapy, hormone-refractory tumors continue to express the androgen receptor (AR) and androgen-regulated genes 1, 2), and it has been suggested that relapsed tumors exhibit a ‘‘partial’’ or ‘‘inappropriate’’ reactivation of AR. Several nonmutually exclusive mechanisms have been proposed to account for inappropriate AR activation. Some androgen-independent tumors contain AR mutations that
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
