Peroxisome proliferator-activated receptor-gamma and retinoid X receptor agonists synergistically suppress proliferation of immortalized endometrial stromal cells.
OBJECTIVE
To examine whether trichostatin A (TSA), a histone deacetylase inhibitor (HDACI), can induce up-regulation of peroxisome proliferator-activating receptor gamma (PPAR gamma) and to see whether LG100268, a retinoid X receptor (RXR) ligand, can inhibit proliferation of endometriotic cells alone or in synergy with ciglitazone, a PPAR gamma agonist.


METHODS
One endometrial stromal cell line and two endometriotic cell lines used as a model system: Western blot analysis to determine whether TSA can up-regulate PPAR gamma expression, and MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) proliferation assay to see whether ciglitazone and LG100268 have any antiproliferative effects individually or jointly.


METHODS
Academic.


METHODS
None.


METHODS
Culture of immortalized endometrial and endometriotic cell lines with TSA, or ciglitazone or LG100268.


METHODS
PPAR gamma protein expression levels in cells treated with or without TSA, and number of viable cells treated with or without ciglitazone, LG100268, or both.


RESULTS
The TSA treatment resulted in up-regulation of PPAR gamma expression in all cell lines in a dose-dependent fashion. Both ciglitazone and LG100268 inhibited proliferation in a dose-dependent manner, and the antiproliferative effects appeared to be synergistic. In addition, endometriotic cells were more sensitive than endometrial stromal cells to LG100268 treatment.


CONCLUSIONS
The up-regulation of PPAR gamma induced by TSA indicates that the action of HDACIs also includes the PPAR gamma signaling pathway, suggesting that the activation of PPAR gamma is a desirable way to contain endometriosis phenotypes. The higher sensitivity of endometriotic cells than their endometrial counterpart to LG100268 treatment suggests that the sensitivity differential could be exploited effectively to eradicate unwanted ectopic endometrial tissues while minimizing the collateral damage to the normal endometrial tissues.
Taussig Cancer Center, Center for Hematology and Oncology Molecular Therapeutics, Cleveland, Ohio, USA.
Yan
Y
Wu
Sun-Wei
SW
Guo
D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D004717:Endometrium / Q000166:cytology / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D009539:Nicotinic Acids / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists*; D011374:Progesterone / Q000494:pharmacology; D047488:Retinoid X Receptors / Q000819:agonists*; D017154:Stromal Cells / Q000166:cytology* / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology*
D009539:Nicotinic Acids; D047495:PPAR gamma; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D013778:Tetrazolium Salts; D013844:Thiazoles; D045162:Thiazolidinediones; D011374:Progesterone; D004958:Estradiol; C022616:thiazolyl blue; C039671:ciglitazone; C095104:LG 100268