Carcinogenesis Advance Access originally published online on May 6, 2009
Carcinogenesis 2009 30(7):1125-1131; doi:10.1093/carcin/bgp112
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-Tocopheryl succinate and derivatives mediate the transcriptional repression of androgen receptor in prostate cancer cells by targeting the PP2A-JNK-Sp1-signaling axis
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy and Comprehensive Cancer Center, Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA
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As part of our effort to understand the mechanism underlying 
-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.
Abbreviations: AEBSF, 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride; AR, androgen receptor; ChIP, chromatin immunoprecipitation; DMSO, dimethyl sulfoxide; EDTA, ethylenediaminetetraacetic acid; ERK, extracellular signal-regulated kinase; FBS, fetal bovine serum; HA, hemagglutinin; JNK, Jun N-terminal kinase; PCR, polymerase chain reaction; PrEC, prostate epithelial cell; PP2A, protein phosphatase 2A; SDS, sodium dodecyl sulfate; TBST, Tris-buffered saline containing 0.1% Tween 20; VES, vitamin E succinate
Received January 21, 2009; revised April 6, 2009; accepted May 2, 2009.