Carcinogenesis Advance Access published online on May 6, 2009
Carcinogenesis, 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, College of Pharmacy, and Comprehensive Cancer Center, The Ohio State University, Columbus, OH
To whom correspondence should be addressed. Ching-Shih Chen, Division of Medicinal Chemistry, College of Pharmacy, Parks Hall, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210. Tel: (614)688-4008; Fax: (614)688-8556; E-mail: chen.844{at}osu.edu.
As part of our effort to understand the mechanism underlying 
-tocopheryl 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 (PP)2A. 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, MAP kinases, NF-
B, 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.
Received January 21, 2009; revised April 6, 2009; accepted May 2, 2009.