Prostate cancer is the second leading cause of non-cutaneous cancer death in American men. According to the American Cancer society about one quarter million new cases are expected to be diagnosed in 2011. Adding to the limitations in the treatment of prostate cancer is the absence of reliable diagnostic marker(s). In order to breach these gaps a better understanding of the molecular pathways that govern prostate cancer is needed. To this end, we have identified Hexim-1, a strong Cdk9 inhibitor, as a novel player in the progression of prostate cancer. The association or dissociation of Hexim-1 from the CyclinT1-Cdk9 heterodimer inhibits or promotes respectively, the serine phosphorylation of the carboxyl-terminus (CTD) of RNA Pol II during transcription elongation. Important to this application is the fact that Cdk9 serine kinase activity targets not only the CTD of RNA Pol II but also, the androgen receptor (AR) and the transforming growth factor ? (TGF-?) signaling pathway. The expression levels of Hexim1 are up regulated in the nuclei during benign hyperplasia, and then are compartmentalized to the cytoplasm in adenocarcinoma of the prostate. In order to achieve the proposed aims, we generated the bi-genic Hexim-1-heterozygous /TRAMP mouse model of prostate cancer as well as prostate cancer cell lines that have been genetically modified by heterozygous deletion of a Hexim 1 allele, such as TRAMP C2/ /Hexim-1 heterozygous.
The specific aims will be: 1. Analysis of the molecular pathways that mediate transcriptional control, expression, and cellular redistribution of Hexim1 during prostate cancer.2. Characterization of Hexim-1 as a regulator of TGF-? cellular functions during prostate cancer. 3. Explore the role of Hexim-1 as a modulator of androgen receptor transcriptional activity during prostate cancer. This study will reveal the molecular components involved in the cross-talk among different players during prostate cancer, such as the Hexim-1, Cdk9, the androgen receptor, and the TGF-? signaling pathway. Taken together, we believe that our proposal will contribute to narrow the gaps that exist between diagnosis and treatment of prostate cancer. The study will identify Hexim-1 as a key modulator at different stages of prostate cancer, and likely support our belief that Hexim-1 inhibition is a strong candidate mechanism for developing new therapy and diagnostic tools.
This proposal will contribute to a better understanding of androgen response in prostate cancer. Hexim-1 may be a new diagnostic tool for definitive differentiation between benign hyperplasia and adenocarcinoma. With further work Hexim -I can be exploited as a new pharmacological target for the treatment of prostate cancer.