Study on identification and application of a novel cancer-associated gene PCA-1 in human prostate carcinoma

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The incidence of prostate cancer has increased recently in Japan. Although there is much information relating to molecular events underlying the etiology of prostate cancer, it is still unclear as to how these genetic alterations occur in the tumorigenesis. For potential gene markers for prostate carcinoma, we have molecularly identified genes showing differential expression between prostate cancers and normal tissues using fluorescent differential display (FDD) analysis. We identified a gene, designated prostate cancer antigen-1 (PCA-1), which shows high mRNA expression in prostate cancer. Database analysis of the deduced amino acid sequence of PCA-1 indicated high similarity to Escherichia coli AlkB, a DNA alkylation damage repair enzyme. By immunohistochemistry, PCA-1 was expressed in a high number of both prostate cancer samples and in the atypical cells within high-grade prostatic intraepithelial neoplasias, but not in benign prostatic hyperplasia or normal adjacent tissues.Ubiquitylation and degradation of FLICE-like inhibitory protein (FLIP) was found to be increased and FLIP-dependent Raf-1/extracellular stress-regulated kinase (ERK)/cyclin D1 signal was inhibited by siRNA gene silencing of endogenous PCA-1, resulting in suppression of epidermal growth factor (EGF)-induced cell growth in the human prostate cancer cell line, DU145. FLIP-dependent signaling from PCA-1 was also apparent on paclitaxel stimulation, and apoptosis was enhanced by PCA-1 knock down through down-regulation of Raf-1/ERK. In LNCaP cells with poor endogenous PCA-1 and FLIP, overexpression of PCA-1 promoted EGF-induced cell growth, while attenuating paclitaxel-induced apoptosis through enhanced FLIP/Raf-1 signaling. Both effects were canceled by silencing of FLIP with siRNA. Taken together, the results indicate that PCA-1 is an essential upstream element in FLIP-dependent Raf-1 signaling, playing a critical role in survival of prostate cancer cells.