Melatonin: The smart molecule that differentially modulates autophagy in tumor and normal placental cells

Abstract

Melatonin has protective roles in normal cells and cytotoxic actions in cancer cells, with effects involving autophagy and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcription factor pathways. Hypoxia/reoxygenation (H/R) induces oxidative damage and apoptosis. These consequences activate autophagy, which degrades damaged cellular content, as well as activates Nrf2 the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcription factor, and thereby the expression of protective genes. Melatonin has protective roles in normal cells and cytotoxic actions in cancer cells, with effects involving autophagy and Nrf2 pathways. The current study shows melatonin to differentially modulate autophagy and Nrf2 pathways in tumor and normal placental cells exposed to H/R. BeWo, a human placental choriocarcinoma cell line, and primary villous cytotrophoblasts isolated from normal term placenta, were maintained in normoxia (8% O2) for 24 h or exposed to hypoxia (0.5% of O2 for 4 h) followed by 20 h of normoxia, creating a situation of H/R, in the presence or absence of 1 mM melatonin. Melatonin induced a 7-fold increase in the activation of 5' adenosine monophosphate-activated protein kinase (AMPK)α, an upstream modulator of autophagy, rising to a 16-fold increase in BeWo cells co-exposed to H/R and melatonin, compared to controls. H/R induced autophagosome formation via the increased expression of Beclin-1 (by 94%) and ATG7 (by 97%) in BeWo cells. Moreover, H/R also induced autophagic activity, indicated by the by the 630% increase in P62, and increased Nrf2 by 314% in BeWo cells. In H/R conditions, melatonin reduced autophagic activity by 74% and Nrf2 expression activation by 300%, leading to BeWo cell apoptosis. In contrast, In human primary villous cytotrophoblasts, H/R induced autophagy and Nrf2, which melatonin further potentiated, thereby affording protection against H/R. This study demonstrates that melatonin differentially modulates autophagy and the Nrf2 pathway in normal vs. tumor trophoblast cells, being cytoprotective in normal cells whilst increasing apoptosis in tumoral trophoblast cells.

Novel classifier orthologs of bovine and human oocytes matured in different melatonin environments

“…PLEKHM1 could regulate the autophagy process which was crucial in the regulation of oocyte metabolism [40][41][42]. SLC47A1 encoded an extrusion protein for drug and toxic metabolites [43].…”

Maternal Melatonin Deficiency Leads to Endocrine Pathologies in Children in Early Ontogenesis

“…Various data obtained in recent decades regarding the mechanisms that determine adverse consequences have proved that only maternal melatonin protects the genetic development program of the mother–placenta–fetus systems from epigenetic damage. By controlling DNA methylation and histone modifications, melatonin prevents changes in the expression of genes that are directly related to the programming of various pathologies’ development [ 170 , 171 , 172 , 173 , 174 ]. As evident from experimental studies, such programming can be prevented or lessened by early administration of melatonin [ 155 , 175 , 176 , 177 ].…”

Autophagy modulating agents as chemosensitizers for cisplatin therapy in cancer

“…The latter is also linked to autophagy induction. Interestingly melatonin was shown to differentially affect autophagic response upon hypoxia/reoxygenation induced oxidative stress - promoting it in normal cells thus acting pro-survival while reducing autophagy in cancer thereby facilitating apoptosis [ 94 ].…”

“… Icariin - flavonoid usually derived from Epimedium sagittatum - anti-cancer, anti-inflammatory, anti-oxiant, anti-apoptotic In vitro : multidrug-resistant ovarian cancer cell - ↑ apoptosis - ↓ autophagic flux [ 93 ] 21. Melatonin - human hormone regulating the sleep-wake cycle - antioxidant - Nrf2 activator - ↑/↓ autophagy (may be cell line specific) In vitro : cervical cancer and head and neck squamous cell carcinoma - ↑ apoptosis - ↓ mitophagy (secondary to ↓ JNK/parkinin activity) - ↑ mitochondrial ROS [ 94 – 96 ] 22. Procyanidins (OCP) - Flavonoids - anti-oxidative, anti-inflammatory, antimicrobial, antiviral and anti-cancer activity In vitro : laryngeal carcinoma - ↑ apoptosis - ↑ autophagy [ 97 ] 23.…”