Abstract
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK, TNFSF12) is a member of the tumor necrosis factor superfamily. 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 and TWEAK actions were studied in two human prostate cancer cell lines, the androgen-independent PC-3 cell line and androgen-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 lines express 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 (TNFα/IFNγ) 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 TNFα/IFNγ/TWEAK induced a higher rate of apoptosis. However, TWEAK or TWEAK/TNFα/IFNγ did not induce apoptosis in presence of bovine fetal serum. TWEAK induced cell death through activation of the Fn14 receptor. Apoptosis was associated with activation of caspase-3, release of mitochondrial cytochrome C and an increased Bax/BclxL ratio. TWEAK/Fn14 pathway activation promotes apoptosis in androgen-independent PC-3 cells under certain culture conditions. Further characterization of the therapeutic target potential of TWEAK/Fn14 for human prostate cancer is warranted.
Highlights
Prostate cancer is the second leading cause of cancer-related death in males [1]
Fn14 expression was negative in normal prostate epithelium, mildly positive in high-grade prostatic intraepithelial neoplasia (PIN) foci and very positive in prostate adenocarcinoma
We studied the expression of TWEAK and Fn14, the TWEAK receptor, in two different human prostate cancer cell lines, PC-3 and LNCaP
Summary
Prostate cancer is the second leading cause of cancer-related death in males [1]. Most cases of prostate cancer present as localized disease and may be cured with surgery and radiation. As is true with most solid malignancies, the development of metastatic disease is lethal. The metastatic phenotype will drive in the development of resistance and disease progression. Systemic treatments in prostate cancer are limited. There were only three FDA-approved chemotherapeutic agents for use in castrate-resistant prostate cancer (estramustine, mitoxantrone, and docetaxel) and two additional agents were approved in 2010 The growth of normal prostate epithelial cells is under the tight control of various growth factors, most notably androgens, castration leads to apoptosis of this cell population. Androgen-depletion has a similar effect on prostate cancers. It is of particular interest to search for agents able to kill androgen-independent prostate cancer cells
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