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

• Published in: Journal of dermatological science Vol. 90; no. 3; pp. 343 - 356
• Main Authors: Chou, Chu-Fang, Hsieh, Yu-Hua, Grubbs, Clinton J., Atigadda, Venkatram R., Mobley, James A., Dummer, Reinhard, Muccio, Donald D., Eto, Isao, Elmets, Craig A., Garvey, W. Timothy, Chang, Pi-Ling
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2018
• Subjects: 9-cis UAB30; Adolescent; Aged, 80 and over; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Bexarotene; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cutaneous T-cell lymphoma; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Down-Regulation; Drug Evaluation, Preclinical; Fatty Acids, Unsaturated - pharmacology; Fatty Acids, Unsaturated - therapeutic use; Humans; Inhibitory Concentration 50; Lymphoma, T-Cell, Cutaneous - drug therapy; Lymphoma, T-Cell, Cutaneous - pathology; Male; Middle Aged; Naphthalenes - pharmacology; Naphthalenes - therapeutic use; p27kip1; Proteasome Endopeptidase Complex - drug effects; Proteasome Endopeptidase Complex - metabolism; PSMA7; Retinoid X Receptors - agonists; Retinoid X Receptors - metabolism; S-Phase Kinase-Associated Proteins - metabolism; Signal Transduction - drug effects; SKP2; Tetrahydronaphthalenes - pharmacology; p27kip1; Bexarotene; SKP2; PSMA7; 9-cis UAB30; Cutaneous T-cell lymphoma
• ISSN: 0923-1811; 1873-569X; 1873-569X
• DOI: 10.1016/j.jdermsci.2018.03.006

•9-cis UA30 (UAB30) induces apoptosis and suppresses proliferation in CTCL cells.•Inhibition of G1 cell-cycle checkpoint by UAB30 involves the SKP2-p27kip1 axis.•UAB30, a RXR-selective agonist, may also have RXR-independent function.•UAB30 can be as effective as bexarotene in treating CTCL.•This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. 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. To assess preclinical efficacy and mechanism of action of UAB30 in the treatment of CTCLs and compare its action with bexarotene. With patient-derived CTCL cell lines, we evaluated UAB30 function in regulating growth, apoptosis, cell cycle check points, and cell cycle-related markers. 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. 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.