Melatonin Induces PERK-ATF4 Unfolded Protein Response and Apoptosis in Human Choriocarcinoma Cells

Bienvenue-Pariseault, Josianne; Sagrillo-Fagundes, Lucas; Wong Yen, Philippe; Stakamatos, Darius; Cohen, Marie et Vaillancourt, Cathy ORCID: https://orcid.org/0000-0003-0543-6244 (2025). Melatonin Induces PERK-ATF4 Unfolded Protein Response and Apoptosis in Human Choriocarcinoma Cells Journal of Pineal Research , vol. 77 , nº 5:e70072. pp. 1-16. DOI: 10.1111/jpi.70072.

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Résumé

Melatonin, an indolamine primarily recognized for regulating circadian rhythms, has also demonstrated notable antitumoral properties. Melatonin induces endoplasmic reticulum (ER) stress, modulates autophagy, and promotes apoptosis in various tumors, including gastric, ovarian, cervical, oral tongue, colorectal, renal, hepatic, and bladder cancer. In placental choriocarcinoma, melatonin reduces cell viability and induces apoptosis by inhibiting autophagy and disrupting the mitochondrial membrane potential. However, its effects on ER stress and the unfolded protein response (UPR) pathway remain unexplored. It is hypothesized here that the proapoptotic effects of melatonin in choriocarcinoma cells occur through the activation of the UPR pathway. The factors implicated in the UPR (PERK, IRE1ɑ, ATF6, GRP78, ATF4, CHOP, P-eIF2α) pathways were evaluated by Western blot, RT-qPCR, and flow cytometry in BeWo (human choriocarcinoma) cells treated with or without melatonin (1 mM). Melatonin significantly increased protein levels of GRP78 (p = 0.0329), IRE1α (p = 0.0394), p-eIF2α (p = 0.0439), ATF4 (p = 0.0267), CHOP (p = 0.0379), Bax and cleaved PARP but did not affect TRAF2 and NFkB protein levels nor XBP1 mRNA splicing. PERK knockdown, via siRNA, prevented the rise in GRP78, p-eIF2α/eIF2α, and ATF4 levels by melatonin. Additionally, melatonin increased early apoptosis in BeWo cells (p = 0.0371) and PERK knockdown increased the susceptibility of BeWo cells to apoptosis when treated with tunicamycin (p = 0.0359), suggesting that ER stress plays a role in BeWo cell survival. This study demonstrates that melatonin activates the PERK-ATF4-P-eIF2α-CHOP pathway and induces early apoptosis in BeWo cells, while PERK deficiency compromises cell survival under ER stress. Our findings suggest that modulating PERK-UPR signaling with melatonin could present a promising therapeutic strategy for cancer, including placental choriocarcinoma.

Type de document:	Article
Informations complémentaires:	This study was supported by grants from the Natural Sciences and Engineering Research Council of Canada (NSERC) (06778‐2019) to C.V. NSERC Graduate Scholarship Doctoral Program and Fonds de recher- che du Québec Nature et Technologie (FRQNT) doctoral training scholarships studentships to JBP and LSG and Undergraduate Student Research Awards for DM received a studentship from Foundation Ar- mand Frappier and from the NSERC Undergraduate Student Research Award studentship.
Mots-clés libres:	BeWo cell; PERK pathway; apoptosis; choriocarcinoma; indolamine; melatonin; unfolded protein response
Centre:	Centre INRS-Institut Armand Frappier
Date de dépôt:	04 juin 2026 15:08
Dernière modification:	04 juin 2026 15:08
URI:	https://espace.inrs.ca/id/eprint/16639

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