α-Tocopheryl succinate and derivatives mediate the transcriptional repression of androgen receptor in prostate cancer cells by targeting the PP2A-JNK-Sp1-signaling axis

Po-Hsien Huang, Dasheng Wang, Hsiao Ching Chuang, Shuo Wei, Samuel K. Kulp, Ching Shih Chen

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33 Citations (Scopus)

Abstract

As part of our effort to understand the mechanism underlying α-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.

Original languageEnglish
Pages (from-to)1125-1131
Number of pages7
JournalCarcinogenesis
Volume30
Issue number7
DOIs
Publication statusPublished - 2009 Jul 15

Fingerprint

Protein Phosphatase 2
Androgen Receptors
Succinic Acid
Vitamin E
Prostatic Neoplasms
Phosphotransferases
Sp1 Transcription Factor
Okadaic Acid
Proteasome Inhibitors
Sp1 kinase
Mitogen-Activated Protein Kinases
Phosphoric Monoester Hydrolases
Pharmaceutical Preparations
Transfection
titanium silicide
Prostate
Plasmids
Epithelial Cells

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Huang, Po-Hsien ; Wang, Dasheng ; Chuang, Hsiao Ching ; Wei, Shuo ; Kulp, Samuel K. ; Chen, Ching Shih. / α-Tocopheryl succinate and derivatives mediate the transcriptional repression of androgen receptor in prostate cancer cells by targeting the PP2A-JNK-Sp1-signaling axis. In: Carcinogenesis. 2009 ; Vol. 30, No. 7. pp. 1125-1131.
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abstract = "As part of our effort to understand the mechanism underlying α-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.",
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α-Tocopheryl succinate and derivatives mediate the transcriptional repression of androgen receptor in prostate cancer cells by targeting the PP2A-JNK-Sp1-signaling axis. / Huang, Po-Hsien; Wang, Dasheng; Chuang, Hsiao Ching; Wei, Shuo; Kulp, Samuel K.; Chen, Ching Shih.

In: Carcinogenesis, Vol. 30, No. 7, 15.07.2009, p. 1125-1131.

Research output: Contribution to journalArticle

TY - JOUR

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AU - Chuang, Hsiao Ching

AU - Wei, Shuo

AU - Kulp, Samuel K.

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