The p75 Neurotrophin Receptor Signaling Pathway as a Novel Therapeutic Target in Prostate Cancer

Daniel Djakiew

The p75NTR exhibits tumor suppressor activity in the prostate by initiating apoptotic cell death. However, cancer cells escape p75NTR mediated apoptosis by down-regulation of its protein expression. Significantly, the gene for p75NTR is intact in prostate cancer cells, so that the loss of protein expression occurs at the level of reduced mRNA stability. In turn, mRNA stability of p75NTR is regulated through the p38MAPK signal transduction pathway. Our laboratory has identified several classes of drugs that stabilize p75NTR mRNA, thereby elevating protein levels that induce apoptotic death of the cancer cells. The identification of existing drugs that regulate components of the p38MAPK signaling pathway, leading to mRNA stability, has provided lead compounds for the development of novel drugs that induce p75NTR dependent cell death. Hence, the aim of this research program is to develop drugs with high specificity for signal transduction components that induce p75NTR dependent apoptosis of prostate cancer.