Melatonin modulation of intracellular signaling pathways in hepatocarcinoma HepG2 cell line: role of the MT1 receptor

Abstract

Melatonin reduces proliferation in many different cancer cell lines. However, studies on the oncostatic effects of melatonin in hepatocarcinoma are limited. We have previously demonstrated that melatonin administration induces cycle arrest, apoptosis, and changes in the expression of its specific receptors in HepG2 human hepatocarcinoma cells. In this study, we used the receptor antagonist luzindole to assess the contribution of MT1 melatonin membrane receptor to melatonin effects on cell viability, mitogen-activated protein kinase (MAPKs) activation, and cAMP levels. Additionally, effects of MT1 inhibition on mRNA levels of cytosolic quinone reductase type-2 (NQO2) receptor and nuclear retinoic acid-related orphan receptor alpha (RORα) were tested. Melatonin, at 1000 and 2500 μm, significantly reduced cell viability. Pre-incubation with luzindole partially inhibited the effects of melatonin on cell viability. Melatonin at 2500 μm significantly reduced cAMP levels, and this effect was partially blocked by luzindole. Both melatonin concentrations increased the expression of phosphorylated p38, ERK, and JNK. ERK activation was completely abolished in the presence of luzindole. NQO2 but not RORα mRNA level significantly increased in luzindole-treated cells. Results obtained provide evidence that the melatonin effects on cell viability and proliferation in HepG2 cells are partially mediated through the MT1 membrane receptor, which seems to be related also with melatonin modulation of cAMP and ERK activation. This study also highlights a possible interplay between MT1 and NQO2 melatonin receptors in liver cancer cells.

Role of melatonin in the regulation of autophagy and mitophagy: A review

“…Since melatonin and autophagy are intimately related to oxidative stress levels, a relationship between them is anticipated. A role of melatonin in regulating apoptosis (programmed cell death type I) has been known for decades, including its differential actions in normal and cancer cells, i.e., melatonin increased apoptosis in cancer cells (Sainz et al, 2003;Motilva et al, 2011;Carbajo-Pescador et al, 2011) while reducing it in normal cells (Gobe and Crane, 2001;Sainz et al, 2003;Stratos et al, 2012). These contrasting findings are now widely accepted by the scientific community, since melatonin's role in modulating oxidative stress by different pathways (direct and indirect) can induce both cellular actions.…”

Effects of combination of melatonin and laser irradiation on ovarian cancer cells and endothelial lineage viability

“…and melatonin receptor-2 (MT-1, MT-2) which are classified as membrane-G-coupled component. Some inherent oncostatic characteristics of melatonin have been proven in many cancerous circumstances, including breast, prostate, colon, bone cancers, and in particular ovary [5]. Various pathways governing the induction of apoptosis, inhibition of cell proliferation, invasion, and metastasis mainly participate through tumor niche [6,7].…”

The impact of melatonin and carbon ion irradiation on cancer stem cells

“…Melatonin (N-acetyl-5-methoxytryptamine), an indole compound synthesized by the pineal gland and many other tissues, is a critical inhibitor of tumors [7][8][9][10][11][12][13][14]. This molecule executes its anticancer effects in various types of cancer due to its pro-apoptotic, anti-proliferative, anti-cell differentiation and anti-angiogenic actions [15,16].…”