Highlights
- •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.
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.
Keywords
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Article info
Publication history
Published online: March 15, 2018
Accepted:
March 8,
2018
Received in revised form:
February 15,
2018
Received:
July 18,
2017
Identification
Copyright
© 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
