An alteration of the
retinoid pathway can influence the development of uterine
leiomyomas in animal models, and
retinoids have shown efficacy in inhibiting the growth of this benign
tumor both in vitro and in vivo. However, the underlying mechanisms and
biological implications are unclear. The present study was based on the demonstration of an accumulation of full-length
retinoid X receptor alpha (RXRalpha) in
leiomyomas that was not associated with a modification of its gene expression. This accumulation was shown to increase the transcription of the RXR-responsive gene
cellular retinoic acid binding protein II (
CRABP-II) and to be linked to the cellular redistribution of the receptor and to its retarded degradation via the
ubiquitin/
proteasome pathway. Accordingly, treatment with a specific
proteasome inhibitor but not with
protease inhibitors strongly inhibited the degradation of full-length RXRalpha in cells deriving from both myometrium and
leiomyoma, but the formation of RXRalpha/
ubiquitin conjugates was differentially regulated between the two cell types. Moreover, full-length RXRalpha accumulated in
leiomyomas was abnormally phosphorylated at
serine/
threonine residues relative to myometrial tissue. The
ligand to RXRalpha,
9-cis-retinoic acid, induced the receptor breakdown in smooth muscle cells deriving from both normal and
tumor tissue, whereas a MAPK-specific inhibitor was able to reduce RXRalpha levels only in
leiomyoma cells. These results suggest that switching of the
ubiquitin/
proteasome-dependent degradation of RXRalpha by phosphorylation in
leiomyomas may be responsible for the accumulation of the receptor and the consequent dysregulation of
retinoic acid target genes. The ability of
retinoids to modify this molecular alteration may be the rationale for their use in the treatment of
leiomyomas.