The significance of TNFAIP8 in prostate cancer response to radiation and docetaxel and disease recurrence

摘要

TNFAIP8 is a NF-κB-inducible, oncogenic molecule. Previous "promoter array" studies have identified differential methylation and regulation of TNFAIP8 in prostate epithelial and cancer cell lines. Here we demonstrate that TNFAIP8 expression is induced by androgen in hormone-responsive LNCaP prostate cancer cells. In athymic mice bearing hormone-refractory PC-3 prostate tumor xenografts, intravenous treatment with a liposomal formulation of TNFAIP8 antisense oligonucleotide (LE-AS5) caused reduced expression of TNFAIP8 in tumor tissues, and a combination of LE-AS5 and radiation or docetaxel treatment resulted in significant inhibition of PC-3 tumor growth as compared to single agents. The immunohistochemical evaluation of TNFAIP8 expression revealed correlation of both cytoplasmic and nuclear TNFAIP8 overexpression with high grade prostatic adenocarcinomas, while nuclear overexpression was found to be an independent predictor of disease recurrence controlling for tumor grade. Increased nuclear TNFAIP8 expression was statistically significantly associated with a 2.44 fold (95 % confidence interval: 1.01-5.91) higher risk of prostate cancer recurrence. Mechanistically, TNFAIP8 seems to function as a scaffold (or adaptor) protein. In the antibody microarray analysis of proteins associated with the TNFAIP8 immune-complex, we have identified Karyopherin alpha2 as a novel binding partner of nuclear TNFAIP8 in PC-3 cells. The Ingenuity Pathway Analysis of the TNFAIP8 interacting proteins suggested that TNFAIP8 influences cancer progression pathways and networks involving integrins and matrix metalloproteinases. Taken together, present studies demonstrate that TNFAIP8 is a novel therapeutic target in prostate cancer, and indicate a potential relationship of the nuclear trafficking of TNFAIP8 with adverse outcomes in a subset of prostate cancer patients. What's new? TNFAIP8, an NF-κB- inducible protein, is an emerging oncogenic molecule of interest, owing to evidence for its possible role in tumor growth and progression. In this study, the first to investigate the therapeutic significance of TNFAIP8, in vivo TNFAIP8 knockdown was found to enhance the efficacy of radiation and docetaxel in a hormone-refractory prostate tumor xenograft model. Furthermore, nuclear TNFAIP8 overexpression was discovered to be an independent predictor of recurrent prostate cancer. The findings indicate that TNFAIP8 may be a key therapeutic target and prognostic marker for prostate cancer.