Abstract 5454: Androgen-independent regulation of cellular signaling, transcriptional activity, and mRNA stability in a cell model of prostate cancer.

Prostate cancer progression relies on the interplay between androgen dependent and independent processes. Depending on the cell type and stimulus, the independent pathway may result in proliferation, progression, or inhibition. It recently has become evident that the molecular mechanisms that drive the differentiation of normal prostate cells towards abnormal proliferation involve multiple signal transduction cascades that often overlap and interact. Through a combination of multiple techniques, including chromatin immunoprecipitation (chIP) and RNA pull-down, we are able to correlate cellular signaling events to androgen receptor transcriptional activity, and how it relates to cancer progression by using growth factors and hormones. In growth factor stimulated LNcap prostate cancer cells, we observed activation of Stat3 and PI3K pathways and reduced transcriptional activity of typical androgen receptor DNA targets, such as prostate-specific antigen (PSA) and cyclin-dependent kinase inhibitor (CDKN1A or p21). However, in estradiol stimulated cells we detected an increase transcriptional activity of the above targets as well as activation of proliferation pathways. Because the androgen receptor and its targets are also regulated by mRNA stability through the UTR, we assessed RNA stability using RNA pull-down assays and RT-PCR. Our results, and those already published, indicate that multiple overlapping signal transduction pathways are involved in the abnormal differentiation of prostate cells; therefore, our use of a combination of tools is advantageous in further defining the model of cancer progression and potential therapies. Citation Format: Suzanne M. Smith, Kay K. Opperman, Barbara J. Kaboord, Peter A. Bell. Androgen-independent regulation of cellular signaling, transcriptional activity, and mRNA stability in a cell model of prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5454. doi:10.1158/1538-7445.AM2013-5454