Role of the PCPH gene in the development and invasiveness of prostate carcinoma

Vicente Notario

PCPH, a gene well conserved among higher organisms, was first identified as an oncogene often activated by environmental carcinogens in rodent model systems. We previously demonstrated that expression of the PCPH oncoprotein rendered cells resistant to the induction of cell death by treatment with radiation or diverse chemotherapeutic drugs. Recent results showed that the PCPH protein is not expressed in normal human prostate, but becomes detectable in benign prostatic hyperplasia (BPH), is highly expressed in prostatic intraepithelial neoplasia (PIN), and remains express at high levels in prostate carcinoma. Furthermore, knockdown of PCPH expression in prostate cancer cells markedly reduced their invasive ability and, concurrently, enhanced the expression and functionality of the androgen receptor. These data identify PCPH not only as a novel, very early marker for prostate cancer progression that could be potentially useful for diagnostic purposes, but also as a molecular target for prostate cancer treatment, because prevention or blockage of PCPH expression would make tumor cells more susceptible to hormonal manipulation and to treatments with radiation or chemotherapeutic drugs. Ongoing experiments focus on: i) understanding the mechanisms by which PCPH expression is maintained off in normal prostate cells and turned on in benign prostatic hyperplasia, ii) identifying and characterizing molecular pathways through which PCPH participates in determining and/or maintaining the malignant characteristics and behavior of prostate tumor cells, and iii) designing molecular tools and small-molecule reagents to block PCPH expression in prostate cancer cells and, consequently, inhibit tumor growth.