ABCC4 is a PGE2 efflux transporter in the ovarian follicle: A mediator of ovulation and a potential non-hormonal contraceptive target.
Humans
Female
Mice
Animals
Dinoprostone
/ metabolism
Contraceptive Agents
/ metabolism
Probenecid
/ metabolism
Ovarian Follicle
/ metabolism
Ovulation
/ physiology
Membrane Transport Proteins
/ metabolism
ATP-Binding Cassette Transporters
/ metabolism
Multidrug Resistance-Associated Proteins
/ genetics
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
revised:
12
01
2023
received:
20
03
2022
accepted:
22
02
2023
entrez:
21
3
2023
pubmed:
22
3
2023
medline:
24
3
2023
Statut:
ppublish
Résumé
The role of prostaglandins (PGs) in the ovulatory process is known. However, the role of the ATP binding cassette subfamily C member 4 (ABCC4), transmembrane PG carrier protein, in ovulation remains unknown. We report herein that ABCC4 expression is significantly upregulated in preovulatory human granulosa cells (GCs). We found that PGE2 efflux in cultured human GCs is mediated by ABCC4 thus regulating its extracellular concentration. The ABCC4 inhibitor probenecid demonstrated effective blocking of ovulation and affects key ovulatory genes in female mice in vivo. We postulate that the reduction in PGE2 efflux caused by the inhibition of ABCC4 activity in GCs decreases the extracellular concentration of PGE2 and its ovulatory effect. Treatment of female mice with low dose of probenecid as well as with the PTGS inhibitor indomethacin or Meloxicam synergistically blocks ovulation. These results support the hypothesis that ABCC4 has an important role in ovulation and might be a potential target for non-hormonal contraception, especially in combination with PGE2 synthesis inhibitors. These findings may fill the gap in understanding the role of ABCC4 in PGE2 signaling, enhance the understanding of ovulatory disorders, and facilitate the treatment and control of fertility.
Identifiants
pubmed: 36943419
doi: 10.1096/fj.202101931RR
doi:
Substances chimiques
Dinoprostone
K7Q1JQR04M
Contraceptive Agents
0
Probenecid
PO572Z7917
Membrane Transport Proteins
0
ATP-Binding Cassette Transporters
0
ABCC4 protein, human
0
Multidrug Resistance-Associated Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e22858Informations de copyright
© 2023 Federation of American Societies for Experimental Biology.
Références
Miller SB. Prostaglandins in health and disease: an overview. Semin Arthritis Rheum. 2006;36:37-49.
Matsumoto H, Ma W, Smalley W, Trzaskos J, Breyer RM, Dey SK. Diversification of cyclooxygenase-2-derived prostaglandins in ovulation and implantation. Biol Reprod. 2001;64:1557-1565.
Olson DM. The role of prostaglandins in the initiation of parturition. Best Pract Res Clin Obstet Gynaecol. 2003;17:717-730.
Murdoch WJ, Hansen TR, McPherson LA. A review-role of eicosanoids in vertebrate ovulation. Prostaglandins. 1993;46:85-115.
Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol. 1998;38:97-120.
Armstrong DT. Prostaglandins and follicular functions. J Reprod Fertil. 1981;62:283-291.
Richards JS. Sounding the alarm-does induction of prostaglandin endoperoxide synthase-2 control the mammalian ovulatory clock? Endocrinology. 1997;138:4047-4048.
Duffy DM. Novel contraceptive targets to inhibit ovulation: the prostaglandin E2 pathway. Hum Reprod Update. 2015;21:652-670.
Armstrong DT, Grinwich DL, Moon YS, Zamecnik J. Inhibition of ovulation in rabbits by intrafollicular injection of indomethacin and prostaglandin F antiserum. Life Sci. 1974;14:129-140.
Lau IF, Saksena SK, Chang MC. Prostaglandins F and ovulation in mice. J Reprod Fertil. 1974;40:467-469.
Lim H, Paria BC, Das SK, et al. Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell. 1997;91:197-208.
Schuster VL. Prostaglandin transport. Prostaglandins Other Lipid Mediat. 2002;68-69:633-647.
Reid G, Wielinga P, Zelcer N, et al. The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci USA. 2003;100:9244-9249.
Lu R, Schuster VL. Molecular cloning of the gene for the human prostaglandin transporter hPGT: gene organization, promoter activity, and chromosomal localization. Biochem Biophys Res Commun. 1998;246:805-812.
Shiraya K, Hirata T, Hatano R, et al. A novel transporter of SLC22 family specifically transports prostaglandins and co-localizes with 15-hydroxyprostaglandin dehydrogenase in renal proximal tubules. J Biol Chem. 2010;285:22141-22151.
Yerushalmi GM, Salmon-Divon M, Yung Y, et al. Characterization of the human cumulus cell transcriptome during final follicular maturation and ovulation. Mol Hum Reprod. 2014;20:719-735.
Yerushalmi GM, Markman S, Yung Y, et al. The prostaglandin transporter (PGT) as a potential mediator of ovulation. Sci Transl Med. 2016;8:338ra368.
Reid G, Wielinga P, Zelcer N, et al. Characterization of the transport of nucleoside analog drugs by the human multidrug resistance proteins MRP4 and MRP5. Mol Pharmacol. 2003;63:1094-1103.
Rius M, Thon WF, Keppler D, Nies AT. Prostanoid transport by multidrug resistance protein 4 (MRP4/ABCC4) localized in tissues of the human urogenital tract. J Urol. 2005;174:2409-2414.
Lin ZP, Zhu YL, Johnson DR, et al. Disruption of cAMP and prostaglandin E2 transport by multidrug resistance protein 4 deficiency alters cAMP-mediated signaling and nociceptive response. Mol Pharmacol. 2008;73:243-251.
Furugen A, Yamaguchi H, Tanaka N, et al. Contribution of multidrug resistance-associated proteins (MRPs) to the release of prostanoids from A549 cells. Prostaglandins Other Lipid Mediat. 2013;106:37-44.
Sedgh G, Bearak J, Singh S, et al. Abortion incidence between 1990 and 2014: global, regional, and subregional levels and trends. Lancet. 2016;388:258-267.
McCann NC, Lynch TJ, Kim SO, Duffy DM. The COX-2 inhibitor meloxicam prevents pregnancy when administered as an emergency contraceptive to nonhuman primates. Contraception. 2013;88:744-748.
Armstrong DT, Grinwich DL. Blockade of spontaneous and LH-induced ovulation in rats by indomethacin, an inhibitor of prostaglandin biosynthesis. Prostaglandins. 1972;1:21-28.
Killick S, Elstein M. Pharmacologic production of luteinized unruptured follicles by prostaglandin synthetase inhibitors. Fertil Steril. 1987;47:773-777.
Bata MS, Al-Ramahi M, Salhab AS, Gharaibeh MN, Schwartz J. Delay of ovulation by meloxicam in healthy cycling volunteers: a placebo-controlled, double-blind, crossover study. J Clin Pharmacol. 2006;46:925-932.
Jesam C, Salvatierra AM, Schwartz JL, Fuentes A, Croxatto HB. Effect of oral administration of a continuous 18 day regimen of meloxicam on ovulation: experience of a randomized controlled trial. Contraception. 2014;90:168-173.
Elizur SE, Lerner-Geva L, Levron J, Shulman A, Bider D, Dor J. Factors predicting IVF treatment outcome: a multivariate analysis of 5310 cycles. Reprod Biomed Online. 2005;10:645-649.
Hourvitz A, Lerner-Geva L, Elizur SE, et al. Role of embryo quality in predicting early pregnancy loss following assisted reproductive technology. Reprod Biomed Online. 2006;13:504-509.
Fadini R, Dal Canto MB, Mignini Renzini M, et al. Effect of different gonadotrophin priming on IVM of oocytes from women with normal ovaries: a prospective randomized study. Reprod Biomed Online. 2009;19:343-351.
Burkholder T, Foltz C, Karlsson E, Linton CG, Smith JM. Health evaluation of experimental laboratory mice. Curr Prot Mouse Biol. 2012;2:145-165.
Kedem A, Ulanenko-Shenkar K, Yung Y, Yerushalmi GM, Maman E, Hourvitz A. Elucidating Decorin's role in the preovulatory follicle. J Ovar Res. 2020;13:15.
Khamsi F, Roberge S. Granulosa cells of the cumulus oophorus are different from mural granulosa cells in their response to gonadotrophins and IGF-I. J Endocrinol. 2001;170:565-573.
Ophir L, Yung Y, Maman E, et al. Establishment and validation of a model for non-luteinized human mural granulosa cell culture. Mol Cell Endocrinol. 2014;384:165-174.
Huynh T, Norris MD, Haber M, Henderson MJ. ABCC4/MRP4: a MYCN-regulated transporter and potential therapeutic target in neuroblastoma. Front Oncol. 2012;2:178.
Russel FG, Koenderink JB, Masereeuw R. Multidrug resistance protein 4 (MRP4/ABCC4): a versatile efflux transporter for drugs and signalling molecules. Trends Pharmacol Sci. 2008;29:200-207.
Copsel S, Garcia C, Diez F, et al. Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation. J Biol Chem. 2011;286:6979-6988.
Hsieh M, Lee D, Panigone S, et al. Luteinizing hormone-dependent activation of the epidermal growth factor network is essential for ovulation. Mol Cell Biol. 2007;27:1914-1924.
Su YQ, Sugiura K, Li Q, Wigglesworth K, Matzuk MM, Eppig JJ. Mouse oocytes enable LH-induced maturation of the cumulus-oocyte complex via promoting EGF receptor-dependent signaling. Mol Endocrinol. 2010;24:1230-1239.
Kim J, Bagchi IC, Bagchi MK. Control of ovulation in mice by progesterone receptor-regulated gene networks. Mol Hum Reprod. 2009;15:821-828.
Fulop C, Szanto S, Mukhopadhyay D, et al. Impaired cumulus mucification and female sterility in tumor necrosis factor-induced protein-6 deficient mice. Development. 2003;130:2253-2261.
Robker RL, Russell DL, Espey LL, Lydon JP, O'Malley BW, Richards JS. Progesterone-regulated genes in the ovulation process: ADAMTS-1 and cathepsin L proteases. Proc Natl Acad Sci USA. 2000;97:4689-4694.
Richards JS, Pangas SA. The ovary: basic biology and clinical implications. J Clin Invest. 2010;120:963-972.
Kohen P, Castro O, Palomino A, et al. The steroidogenic response and corpus luteum expression of the steroidogenic acute regulatory protein after human chorionic gonadotropin administration at different times in the human luteal phase. J Clin Endocrinol Metab. 2003;88:3421-3430.
Doody KJ, Lorence MC, Mason JI, Simpson ER. Expression of messenger ribonucleic acid species encoding steroidogenic enzymes in human follicles and corpora lutea throughout the menstrual cycle. J Clin Endocrinol Metab. 1990;70:1041-1045.
Fortier MA, Krishnaswamy K, Danyod G, Boucher-Kovalik S, Chapdalaine P. A postgenomic integrated view of prostaglandins in reproduction: implications for other body systems. J Physiol Pharmacol. 2008;59(Suppl 1):65-89.
Wissing ML, Kristensen SG, Andersen CY, et al. Identification of new ovulation-related genes in humans by comparing the transcriptome of granulosa cells before and after ovulation triggering in the same controlled ovarian stimulation cycle. Hum Reprod. 2014;29:997-1010.
Russell DL, Robker RL. Molecular mechanisms of ovulation: co-ordination through the cumulus complex. Hum Reprod Update. 2007;13:289-312.
Choi Y, Wilson K, Hannon PR, et al. Coordinated regulation among progesterone, prostaglandins, and EGF-like factors in human ovulatory follicles. J Clin Endocrinol Metab. 2017;102:1971-1982.
Choi Y, Rosewell KL, Brännström M, Akin JW, Curry TE Jr, Jo M. FOS, a critical downstream mediator of PGR and EGF signaling necessary for ovulatory prostaglandins in the human ovary. J Clin Endocrinol Metab. 2018;103:4241-4252.
Gelhaus SL, Gilad O, Hwang WT, Penning TM, Blair IA. Multidrug resistance protein (MRP) 4 attenuates benzo[a]pyrene-mediated DNA-adduct formation in human bronchoalveolar H358 cells. Toxicol Lett. 2012;209:58-66.
Leggas M, Adachi M, Scheffer GL, et al. Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Mol Cell Biol. 2004;24:7612-7621.
Morgan JA, Cheepala SB, Wang Y, et al. Deregulated hepatic metabolism exacerbates impaired testosterone production in Mrp4-deficient mice. J Biol Chem. 2012;287:14456-14466.
Duffy DM, Stouffer RL. Follicular administration of a cyclooxygenase inhibitor can prevent oocyte release without alteration of normal luteal function in rhesus monkeys. Hum Reprod. 2002;17:2825-2831.
Tomac J, Cekinovic D, Arapovic J. Biology of the Corpus luteum. Period Biol. 2011;113:43-49.
Sogn JH, Curry TE Jr, Brannstrom M, et al. Inhibition of follicle-stimulating hormone-induced ovulation by indomethacin in the perfused rat ovary. Biol Reprod. 1987;36:536-542.
Elvin JA, Yan C, Matzuk MM. Growth differentiation factor-9 stimulates progesterone synthesis in granulosa cells via a prostaglandin E2/EP2 receptor pathway. Proc Natl Acad Sci U S A. 2000;97:10288-10293.
Peluffo MC, Stanley J, Braeuer N, et al. A prostaglandin E2 receptor antagonist prevents pregnancies during a preclinical contraceptive trial with female macaques. Hum Reprod. 2014;29:1400-1412.
Ben-Ami I, Freimann S, Armon L, et al. PGE2 up-regulates EGF-like growth factor biosynthesis in human granulosa cells: new insights into the coordination between PGE2 and LH in ovulation. Mol Hum Reprod. 2006;12:593-599.
Shimada M, Hernandez-Gonzalez I, Gonzalez-Robayna I, Richards JS. Paracrine and autocrine regulation of epidermal growth factor-like factors in cumulus oocyte complexes and granulosa cells: key roles for prostaglandin synthase 2 and progesterone receptor. Mol Endocrinol. 2006;20:1352-1365.
Duffy DM, Ko C, Jo M, Brannstrom M, Curry TE. Ovulation: parallels with inflammatory processes. Endocr Rev. 2019;40:369-416.
Massai MR, Forcelledo ML, Brache V, et al. Does meloxicam increase the incidence of anovulation induced by single administration of levonorgestrel in emergency contraception? A pilot study. Hum Reprod. 2007;22:434-439.