Clinical Sciences, University of Kentucky, Lexington, KY, USA.
Apoptosis. 2010 Feb;15(2):153-61. doi: 10.1007/s10495-009-0416-9.
The tumor necrosis factor (TNF) receptor super family comprises of members that induce two distinct signaling cascades, leading to either cell survival or apoptosis. However, in prostate cancer (PCa), TNF-mediated prosurvival signaling is the predominant pathway that leads to cell survival and resistance to therapy. Although inhibition of TNF signaling by pharmacological agents or monoclonal antibodies has gained importance in the field of cancer therapy, toxicity to normal cells has impaired their extensive use for cancer treatment. We previously identified a natural, nontoxic compound psoralidin that inhibited viability and induced apoptosis in androgen independent prostate cancer (AIPC) cells. Thus, the goal of our study is to investigate whether psoralidin inhibits TNF-mediated prosurvival signaling in AIPC cells. Our results suggest that psoralidin inhibits constitutive and TNF-induced expression of TNF-alpha and its downstream prosurvival signaling molecules such as NF-kappaB and Bcl-2 in AIPC cells. On the other hand, psoralidin simultaneously induces the death receptor (DR)-mediated apoptotic signaling eventually causing the activation of caspase cascade and resultant induction of apoptosis. Oral administration of psoralidin inhibits expression of TNF-alpha and NF-kappaB/p65 in tumor sections, resulting in tumor regression in PC-3 xenografts. Our results suggest that psoralidin inhibits TNF-mediated survival signaling in AIPC and thus is a potent therapeutic agent for prostate cancer.
肿瘤坏死因子（TNF）受体超家族包括能够诱导两种不同信号级联反应的成员，导致细胞存活或凋亡。然而，在前列腺癌（PCa）中，TNF 介导的生存信号是导致细胞存活和对治疗产生抗性的主要途径。尽管通过药理试剂或单克隆抗体抑制 TNF 信号已在癌症治疗领域得到重视，但对正常细胞的毒性限制了它们在癌症治疗中的广泛应用。我们之前已经确定了一种天然的、无毒的化合物补骨脂素，它可以抑制雄激素非依赖性前列腺癌细胞（AIPC）的活力并诱导其凋亡。因此，我们研究的目的是探讨补骨脂素是否可以抑制 AIPC 细胞中 TNF 介导的生存信号。我们的结果表明，补骨脂素抑制 AIPC 细胞中 TNF-α及其下游生存信号分子（如 NF-κB 和 Bcl-2）的组成型和 TNF 诱导表达。另一方面，补骨脂素同时诱导死亡受体（DR）介导的凋亡信号，最终导致半胱天冬酶级联的激活和随后的凋亡诱导。补骨脂素的口服给药抑制肿瘤组织中 TNF-α和 NF-κB/p65 的表达，导致 PC-3 异种移植瘤的肿瘤消退。我们的结果表明，补骨脂素抑制 AIPC 中的 TNF 介导的生存信号，因此是治疗前列腺癌的有效治疗剂。
