Department of Urology Research/Biochemistry, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Cancer Res. 2009 Dec 15;69(24):9448-56. doi: 10.1158/0008-5472.CAN-09-1903.
By using LNCaP and its derivative cell lines, we first observed an association between tumor necrosis factor-alpha (TNF-alpha) resistance and hormone independence. Moreover, we found that the expression of tumor necrosis factor receptor-associated death domain (TRADD) was reduced in androgen deprivation-independent cells compared with that in androgen deprivation-dependent cells. TRADD is a crucial transducer for TNF-alpha-induced nuclear factor-kappaB (NF-kappaB) activation. Knocking down TRADD expression in LNCaP cells impaired TNF-alpha-induced NF-kappaB activation and androgen receptor repression, whereas overexpression of TRADD in C4-2B cells restored their sensitivity to TNF-alpha. Finally, we found that androgen deprivation reduces TRADD expression in vitro and in vivo, suggesting that androgen deprivation therapy may promote the development of TNF-alpha resistance by reducing TRADD expression during prostate cancer progression.
通过使用 LNCaP 及其衍生细胞系，我们首先观察到肿瘤坏死因子-α（TNF-α）耐药性与激素独立性之间存在关联。此外，我们发现与雄激素剥夺依赖性细胞相比，雄激素剥夺非依赖性细胞中肿瘤坏死因子受体相关死亡结构域（TRADD）的表达降低。TRADD 是 TNF-α 诱导核因子-κB（NF-κB）激活的关键转导子。在 LNCaP 细胞中敲低 TRADD 表达会损害 TNF-α诱导的 NF-κB 激活和雄激素受体抑制，而在 C4-2B 细胞中过表达 TRADD 则恢复了它们对 TNF-α的敏感性。最后，我们发现雄激素剥夺在体外和体内均可降低 TRADD 的表达，这表明在前列腺癌进展过程中，雄激素剥夺治疗可能通过降低 TRADD 的表达来促进 TNF-α 耐药性的发展。
