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Anti-Tumorous Actions of Melatonin in Placental Choriocarcinoma Cells : Implications of UPR Pathway, Autophagy and Apoptosis.

Bienvenue-Pariseault, Josianne; Sagrillo-Fagundes, Lucas; Vaillancourt, Cathy . Anti-Tumorous Actions of Melatonin in Placental Choriocarcinoma Cells : Implications of UPR Pathway, Autophagy and Apoptosis. In: 66th Annual Scientific Meeting of the Society of Reproduction Investigation (SRI), 12-16 mars 2019, Paris, France.

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Résumé

Introduction:Context: Placental choriocarcinoma originates from the malignant transformation of trophoblasts. It occurs in 1 pregnancy in 40 000. The woman affected by this cancer is treated with chemotherapy that has teratogenic risk for subsequent pregnancy. Safer anti-tumorous compound is needed to treat this cancer. Melatonin, an indolamine produced by the pineal gland but also by the placenta, is known for its role in circadian cycle but also for its anti-cancerous properties. Due to its low toxicity to normal cells and due to the fact that placental cells have its receptors, melatonin is a promising treatment for placental choriocarcinoma. It has been demonstrated that exogenous melatonin, by its actions on endoplasmic reticulum (ER) stress, autophagy and apoptosis, has a cytotoxic effect on ovarian and breast cancer cells. These effects on placental choriocarcinoma cells (BeWo) has never been established, though. Hypothesis: Melatonin has anti-tumorous actions on BeWo cells. Objectives: Determine in BeWo cells, if melatonin has an effect on: 1) the ER stress unfolded protein response (UPR), 2) autophagy and 3) apoptosis.

Methods: BeWo cells were treated with or without melatonin (1 mM) under normoxic condition (8% O2). Factors implicated in ER stress, autophagy and apoptosis were analyzed by Western blot, immunofluorescence, and RT-qPCR.

Results: Melatonin, compared to DMSO (vehicle), significantly increases protein levels of GRP78 (400%; P=0,0172), IRE1α (257%; P=0,0293), PERK (190%; P=0,0379), P-eIF2α (108%; P=0,0148), ATF4 (85%; P=0,0643) and has a slight tendency to increase CHOP (58%; P=0,1392), but doesn’t affect TRAF2, NFkB and the splicing of the XBP1 mRNA. Melatonin increases phosphorylation of AMPK (670%; P=0,0070) and the protein level of ATG7 (97%; P=<0,0001), but has no effect on the autophagic flux. Also, it has a slight tendency to increase protein levels of clived Parp (73%, P=0,0811) and Bax/Bcl2 ratio (66%, P=0,0738).

Conclusion: This study suggests that anti-cancerous action of melatonin in placental choriocarcinoma cells is mediated by the induction of ER stress UPR’s PERK- P-eIF2α-ATF4-CHOP pathway which leads to apoptosis. Our results add impact to the fact that melatonin is a potent anti-tumorous molecule.

Type de document: Document issu d'une conférence ou d'un atelier
Informations complémentaires: Reproductive Sciences (2019), 26 (suppl.1), p.39A F-142 Affiche scientifique
Mots-clés libres: -
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 21 nov. 2019 16:13
Dernière modification: 21 nov. 2019 16:13
URI: http://espace.inrs.ca/id/eprint/8195

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