The retinoid X receptor agonist, 9-cis UAB30, inhibits cutaneous T-cell lymphoma proliferation through the SKP2-p27kip1 axis.

Academic Article

Abstract

  • BACKGROUND: Bexarotene (Targretin┬«) is currently the only FDA approved retinoid X receptor (RXR) -selective agonist for the treatment of cutaneous T-cell lymphomas (CTCLs). The main side effects of bexarotene are hypothyroidism and elevation of serum triglycerides (TGs). The novel RXR ligand, 9-cis UAB30 (UAB30) does not elevate serum TGs or induce hypothyroidism in normal subjects. OBJECTIVES: To assess preclinical efficacy and mechanism of action of UAB30 in the treatment of CTCLs and compare its action with bexarotene. METHODS: With patient-derived CTCL cell lines, we evaluated UAB30 function in regulating growth, apoptosis, cell cycle check points, and cell cycle-related markers. RESULTS: Compared to bexarotene, UAB30 had lower half maximal inhibitory concentration (IC50) values and was more effective in inhibiting the G1 cell cycle checkpoint. Both rexinoids increased the stability of the cell cycle inhibitor, p27kip1 protein, in part, through targeting components involved in the ubiquitination-proteasome system: 1) decreasing SKP2, a F-box protein that binds and targets p27kip1 for degradation by 26S proteasome and 2) suppressing 20S proteasome activity (cell line-dependent) through downregulation of PSMA7, a component of the 20S proteolytic complex in 26S proteasome. CONCLUSIONS: UAB30 and bexarotene induce both early cell apoptosis and suppress cell proliferation. Inhibition of the G1 to S cell cycle transition by rexinoids is mediated, in part, through downregulation of SKP2 and/or 20S proteasome activity, leading to increased p27kip1 protein stability. Because UAB30 has minimal effect in elevating serum TGs and inducing hypothyroidism, it is potentially a better alternative to bexarotene for the treatment of CTCLs.
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    Keywords

  • 9-cis UAB30, Bexarotene, Cutaneous T-cell lymphoma, PSMA7, SKP2, p27kip1, Adolescent, Aged, 80 and over, Antineoplastic Agents, Apoptosis, Bexarotene, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p27, Down-Regulation, Drug Evaluation, Preclinical, Fatty Acids, Unsaturated, Humans, Inhibitory Concentration 50, Lymphoma, T-Cell, Cutaneous, Male, Middle Aged, Naphthalenes, Proteasome Endopeptidase Complex, Retinoid X Receptors, S-Phase Kinase-Associated Proteins, Signal Transduction, Tetrahydronaphthalenes
  • Digital Object Identifier (doi)

    Author List

  • Chou C-F; Hsieh Y-H; Grubbs CJ; Atigadda VR; Mobley JA; Dummer R; Muccio DD; Eto I; Elmets CA; Garvey WT
  • Start Page

  • 343
  • End Page

  • 356
  • Volume

  • 90
  • Issue

  • 3