Prostaglandin EP2 receptor signaling protects human trabecular meshwork cells from apoptosis induced by ER stress through down-regulation of p53.
E-prostanoid receptor subtype 2 (EP2) agonists are currently under clinical development as hypotensive agents for the treatment of ocular hypertension. However, the effects of EP2 receptor agonists on trabecular meshwork (TM) alterations leading to primary open-angle glaucoma (POAG) are still unknown. Here, we evaluated whether EP2 receptor activation exhibits protective functions on TM cell death induced by endoplasmic reticulum (ER) stress. We show that the EP2 receptor agonist butaprost protects TM cell death mediated by the ER stress inducer tunicamycin through a cyclic AMP (cAMP)-dependent mechanism, but independent of the classical cAMP sensors, protein kinase A and exchange proteins activated by cAMP. The ER stress-induced intrinsic apoptosis inhibited by the EP2 receptor agonist was correlated with a decreased accumulation of the cellular stress sensor p53. In addition, p53 down-regulation was associated with inhibition of its transcriptional activity, which led to decreased expression of the pro-apoptotic p53-upregulated modulator of apoptosis (PUMA). The stabilization of p53 by nutlin-3a abolished butaprost-mediated cell death protection. In conclusion, we showed that EP2 receptor activation protects against ER stress-dependent mitochondrial apoptosis through down-regulation of p53. The specific inhibition of this pathway could reduce TM alterations observed in POAG patients.
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, 75012 Paris, France; Sanofi Research & Development, Translational Sciences Unit, Chilly-Mazarin 91380, France. Electronic address: georges.kalouche@sanofi.com.
Georges
G
Kalouche
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, 75012 Paris, France.
Céline
C
Boucher
Sanofi Research & Development, Translational Sciences Unit, Chilly-Mazarin 91380, France.
Annick
A
Coste
Sanofi Research & Development, Oncology, Vitry-Sur-Seine 94400, France.
Laurent
L
Debussche
Sanofi Research & Development, Translational Sciences Unit, Chilly-Mazarin 91380, France.
Cécile
C
Orsini
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, 75012 Paris, France; Quinze-Vingts National Ophthalmology Hospital, Paris 75012, France.
Christophe
C
Baudouin
Sanofi Research & Development, Ophthalmology, Paris 75012, France.
Thomas
T
Debeir
Sanofi Research & Development, Translational Sciences Unit, Chilly-Mazarin 91380, France.
Xavier
X
Vigé
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, 75012 Paris, France.
William
W
Rostène
D000328:Adult; D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014129:Trabecular Meshwork / Q000473:pathology*; D051742:Transcription Factor CHOP / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects
D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D020662:Guanine Nucleotide Exchange Factors; D006360:Heat-Shock Proteins; D011518:Proto-Oncogene Proteins; D058307:Receptors, Prostaglandin E, EP2 Subtype; D016159:Tumor Suppressor Protein p53; D014415:Tunicamycin; D051742:Transcription Factor CHOP; D045304:Cytochromes c; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020169:Caspases; D000527:Alprostadil; C048491:butaprost
EP2 receptor; ER stress; PUMA; Trabecular meshwork cells; cAMP; p53