Inflammatory cytokines and survival factors from serum modulate tweak-induced apoptosis in PC-3 Prostate Cancer Cells

摘要

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK, TNFSF12) is a member of the tumor necrosis factorsuperfamily. TWEAK activates the Fn14 receptor, and may regulate cell death, survival and proliferation in tumor cells.However, there is little information on the function and regulation of this system in prostate cancer. Fn14 expression andTWEAK actions were studied in two human prostate cancer cell lines, the androgen-independent PC-3 cell line andandrogen-sensitive LNCaP cells. Additionally, the expression of Fn14 was analyzed in human biopsies of prostate cancer.Fn14 expression is increased in histological sections of human prostate adenocarcinoma. Both prostate cancer cell linesexpress constitutively Fn14, but, the androgen-independent cell line PC-3 showed higher levels of Fn14 that the LNCaP cells.Fn14 expression was up-regulated in PC-3 human prostate cancer cells in presence of inflammatory cytokines (TNFa/IFNc)as well as in presence of bovine fetal serum. TWEAK induced apoptotic cell death in PC-3 cells, but not in LNCaP cells.Moreover, in PC-3 cells, co-stimulation with TNFa/IFNc/TWEAK induced a higher rate of apoptosis. However, TWEAK orTWEAK/TNFa/IFNc did not induce apoptosis in presence of bovine fetal serum. TWEAK induced cell death throughactivation of the Fn14 receptor. Apoptosis was associated with activation of caspase-3, release of mitochondrial cytochromeC and an increased Bax/BclxL ratio. TWEAK/Fn14 pathway activation promotes apoptosis in androgen-independent PC-3cells under certain culture conditions. Further characterization of the therapeutic target potential of TWEAK/Fn14 for humanprostate cancer is warranted.