α-Tocopheryl succinate and derivatives mediate the transcriptional repression of androgen receptor in prostate cancer cells by targeting the PP2A-JNK-Sp1-signaling axis
α-Tocopheryl succinate and derivatives mediate the transcriptional repression of androgen receptor in prostate cancer cells by targeting the PP2A-JNK-Sp1-signaling axis
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DOI：
10.1093/carcin/bgp112
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发表时间：
2009-07-01
期刊：
影响因子：
4.7
通讯作者：
Chen, Ching-Shih
中科院分区：
文献类型：
--
作者：
Huang, Po-Hsien;Wang, Dasheng;Chen, Ching-Shih
作为了解α-生育酚琥珀酸酯[维生素E琥珀酸酯(VES)]介导的抗肿瘤作用的机制的一部分，我们研究了VES抑制前列腺癌细胞雄激素受体(AR)表达的信号通路。VES及其截断的衍生物TS-1在更大程度上介导了AR在前列腺癌细胞中的转录抑制，但在正常前列腺上皮细胞中却没有；这一发现突显了正常细胞和恶性细胞对这些药物的抗增殖作用的不同敏感性。这种AR抑制可归因于VES和TS-1促进转录因子Sp1蛋白酶体降解的能力。蛋白酶体抑制剂或Sp1的异位表达保护细胞免受药物诱导的AR消融，这一发现证实了这一机制联系。此外，有证据表明，VES和TS-1对Sp1的失稳是由于蛋白磷酸酶2A(PP2A)的磷酸酶活性增加导致Jun氨基末端激酶(JNKs)失活所致。用显性阴性的JNK1质粒稳定地转染LNCaP细胞可模拟药物诱导的Sp1抑制，而JNK激酶活性的组成性激活或冈田酸抑制PP2A活性可保护Sp1免受VES和TS-1诱导的降解。从机制的角度来看，VES和TS-1激活PP2A活性的能力突显了它们在多种信号机制中的广泛作用，包括Akt、丝裂原激活的蛋白激酶、核因子kappaB、Sp1和AR。这种多效性效应与低毒性相结合，表明了将TS-1开发为有效的PP2A激活剂用于癌症治疗的翻译潜力。
As part of our effort to understand the mechanism underlying alpha-tocopheryl succinate [vitamin E succinate (VES)]-mediated antitumor effects, we investigated the signaling pathway by which VES suppresses androgen receptor (AR) expression in prostate cancer cells. VES and, to a greater extent, its truncated derivative TS-1 mediated transcriptional repression of AR in prostate cancer cells but not in normal prostate epithelial cells; a finding that underscores the differential susceptibility of normal versus malignant cells to the antiproliferative effect of these agents. This AR repression was attributable to the ability of VES and TS-1 to facilitate the proteasomal degradation of the transcription factor Sp1. This mechanistic link was corroborated by the finding that proteasome inhibitors or ectopic expression of Sp1 protected cells against drug-induced AR ablation. Furthermore, evidence suggests that the destabilization of Sp1 by VES and TS-1 resulted from the inactivation of Jun N-terminal kinases (JNKs) as a consequence of increased phosphatase activity of protein phosphatase 2A (PP2A). Stable transfection of LNCaP cells with the dominant-negative JNK1 plasmid mimicked drug-induced Sp1 repression, whereas constitutive activation of JNK kinase activity or inhibition of PP2A activity by okadaic acid protected Sp1 from VES- and TS-1-induced degradation. From a mechanistic perspective, the ability of VES and TS-1 to activate PP2A activity underscores their broad spectrum of effects on multiple signaling mechanisms, including those mediated by Akt, mitogen-activated protein kinases, nuclear factor kappaB, Sp1 and AR. This pleiotropic effect in conjunction with low toxicity suggests the translational potential for developing TS-1 into potent PP2A-activating agents for cancer therapy.