Induced Expression of Androgen Receptor in Androgen Independent Prostate Cancer Cells Using an I kBa 'Super Repressor'

摘要

Advanced prostate cancer continues to kill 29,000 men annually in the United States. Despite strides in obtaining extended remissions, there is still no curative therapy for this devastating disease. While most prostate cancers are responsive to androgens and while androgen withdrawal is the main form of treatment, the failure of primary hormone therapy is attributed to androgen independent tumor expansion. Mechanisms for the transition from androgen sensitive to androgen refractory disease are currently not well understood. We proposed to investigate the role of TNF-alpha mediated NF-kB signaling in androgen-sensitive and -insensitive prostate cancer, as many androgen independent prostate cancer cell lines exhibit resistance to this pathway and as TNF-alpha is detected at high serum levels in relapsing prostate cancer patients compared to those in remission or untreated. During this current funding period we experienced difficulties in engineering dual luciferase and PSA-IxBalpha 'super repressor' expressing cell lines for proposed in vivo experiments. We report characterization of PAR1 as a novel activator of NF-kB signaling and generation of an androgen-insensitive cell line from androgen receptor wildtype, androgen-sensitive VCaP. With recent access to new transfection technology, we anticipate swift creation of necessary sublines and will be poised to evaluate these novel insights of androgen interactions in vivo.