Altered retinoid uptake and action contributes to cell survival in endometriosis.
BACKGROUND
Retinoic acid (RA) controls multiple biological processes via exerting opposing effects on cell survival. Retinol uptake into cells is controlled by stimulated by RA 6 (STRA6). RA is then produced from retinol in the cytosol. Partitioning of RA between the nuclear receptors RA receptor α and peroxisome-proliferator-activated receptor β/δ is regulated by cytosol-to-nuclear shuttling proteins cellular RA binding protein 2 (CRABP2) and fatty acid binding protein 5 (FABP5), which induce apoptosis or enhance survival, respectively. The roles of these mechanisms in endometrium or endometriosis remain unknown.


OBJECTIVE
The aim was to determine the regulation of retinoid uptake and RA action in primary stromal cells from endometrium (n = 10) or endometriosis (n = 10).


RESULTS
Progesterone receptor was necessary for high STRA6 and CRABP2 expression in endometrial stromal cells. STRA6, which was responsible for labeled retinoid uptake, was strikingly lower in endometriotic cells compared to endometrial cells. CRABP2 knockdown in endometrial cells increased survival, and FABP5 knockdown in endometriotic cells decreased survival without altering the expression of downstream nuclear retinoic acid receptor α and peroxisome-proliferator-activated receptor β/δ.


CONCLUSIONS
In endometrial stromal cells, progesterone receptor up-regulates expression of STRA6 and CRABP2, which control retinol uptake and growth-suppressor actions of RA. In endometriotic stromal cells, decreased expression of these genes leads to decreased retinol uptake and dominant FABP5-mediated prosurvival activity.
Pavone
Mary Ellen
ME
Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois 60611, USA.
Reierstad
Scott
S
Sun
Hui
H
Milad
Magdy
M
Bulun
Serdar E
SE
Cheng
You-Hong
YH
D000328:Adult; D000704:Analysis of Variance; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D004715:Endometriosis / Q000235:genetics / Q000378:metabolism*; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D010049:Ovarian Diseases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation
D008565:Membrane Proteins; D034741:RNA, Small Interfering; D011980:Receptors, Progesterone; D018168:Receptors, Retinoic Acid; C519685:STRA6 protein, human; C082928:retinoic acid binding protein II, cellular; D014212:Tretinoin