title: Punicalagin promotes autophagy to protect primary human syncytiotrophoblasts from apoptosis.
abstract: Punicalagin is a prominent polyphenol in pomegranate juice that protects cultured syncytiotrophoblasts from stress-induced apoptosis. Here, we test the hypothesis that punicalagin has this effect by inhibiting the mTOR kinase pathway to enhance autophagic turnover and limit apoptosis in cultured primary human syncytiotrophoblasts. In syncytiotrophoblasts, starvation, rapamycin, or punicalagin all decreased the expression of phosphorylated ribosomal protein S6, a downstream target of the mTOR kinase, and of the autophagy markers, LC3-II and p62. In contrast, in the presence of bafilomycin, an inhibitor of late stages of autophagy and degradation in the autophagolysosome, syncytiotrophoblasts exposed to starvation, rapamycin, or punicalagin all showed increased levels of LC3-II and p62. The number of LC3-II punctae also increased in punicalagin-treated syncytiotrophoblasts exposed to chloroquine, another inhibitor of autophagic degradation, and punicalagin increased the number of lysosomes. The apoptosis-reducing effect of punicalagin was attenuated by inhibition of autophagy using bafilomycin or knockdown of the autophagy related gene, ATG16L1. Collectively, these data support the hypothesis that punicalagin modulates the crosstalk between autophagy and apoptosis to promote survival in cultured syncytiotrophoblasts.
authors.affiliation: Department of Obstetrics and GynecologyWashington University School of Medicine, 4566 Scott Avenue, St Louis, Missouri 63110, USALaboratory for Reproductive ImmunologyHospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China Department of Obstetrics and GynecologyWashington University School of Medicine, 4566 Scott Avenue, St Louis, Missouri 63110, USALaboratory for Reproductive ImmunologyHospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and GynecologyWashington University School of Medicine, 4566 Scott Avenue, St Louis, Missouri 63110, USALaboratory for Reproductive ImmunologyHospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China chenb@wudosis.wustl.edu.
authors.forename: Baosheng
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and GynecologyWashington University School of Medicine, 4566 Scott Avenue, St Louis, Missouri 63110, USALaboratory for Reproductive ImmunologyHospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Longtine
authors.affiliation: Department of Obstetrics and GynecologyWashington University School of Medicine, 4566 Scott Avenue, St Louis, Missouri 63110, USALaboratory for Reproductive ImmunologyHospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China.
authors.forename: D Michael
authors.initials: DM
authors.lastname: Nelson
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology*; D011247:Pregnancy; D061251:Primary Cell Culture; D020123:Sirolimus / Q000494:pharmacology; D014327:Trophoblasts / Q000187:drug effects* / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D047348:Hydrolyzable Tannins; C115642:punicalagin; D020123:Sirolimus