Melatonin Differentially Modulates NF-кB Expression in Breast and Liver Cancer Cells

Abstract

Background NF-kB (nuclear factor kappa B) is a transcription factor composed of two subunits, p50 and p65, which plays a key role in the inflammatory process. Melatonin has oncostatic, antiangiogenic and antimetastatic properties, and some recent studies have indicated an inhibitory effect of melatonin on NF-kB in some types of cancer. This work aims to investigate the effects of melatonin treatment on the expression of NF-kB in breast and liver cancer models. Methods The breast cancer xenographic model was performed using female Balb/c nude athymic mice injected with MDA-MB-231 cells. The animals were treated with 40 mg/Kg of melatonin for 21 days. Volume of the tumors was measured with a digital capiler. Hepatocarcinoma model was developed by using the HepG2 cells in vitro, treated with 1 mM melatonin for 24 h. The expression of NF-kB protein was verified by immunohistochemistry and immunocytochemistry and quantified by optical densitometry, in vivo study and in vitro study, respectively. NF-kB gene expression was performed by quantitative RT-PCR. Results The breast cancer xenografts nude mice treated with melatonin showed reduced tumor size (P=0.0022). There was a decrease in NF-kB protein staining (P=0.0027) and gene expression (P=0.0185) in mice treated with melatonin. The opposite results were observed for the hepatocarcinoma model. HepG2 cells treated with melatonin showed an increase in the NF-kB immunostaining when compared to control cells (P=0.0042). Conclusion Our results indicated that treatment with melatonin was able to decrease both gene and protein expressions of NF-kB in breast cancer cells and, conversely, increase the transcription factor protein expression in hepatocarcinoma cells. These data highlighted a double role in the expression of NF-kB, depending on the cell type. Further studies are needed to better elucidate the action of melatonin in NF-kB, since this transcription factor acts on different signaling pathways that are fundamental for carcinogenesis.

Melatonin: An Anti-Tumor Agent in Hormone-Dependent Cancers

“…Several protooncogenes (such as c-Myc) growth factors (TGF α ) and transcription factors (NF-k β ) targeted by the estrogen signaling pathways are modulated by this concentration of melatonin in breast cancer cells [ 42 ]. Similar results (at pharmacological doses) have been obtained in vivo , in Balb/c nude athymic mice (melatonin dose: 40 mg/kg of body weight, 5 days/week during 21 days) [ 43 ]. Estradiol and estrogen-like endocrine disrupting chemicals promote cell-cycle progression by increasing the levels of cell-cycle-related proteins such as cyclin D1 and cathepsin D, whereas it decreases the levels of p21 [ 44 – 46 ].…”

Melatonin as an Antitumor Agent against Liver Cancer: An Updated Systematic Review

“…This was caused by a mechanism associated with alleviation on oxidative and nitrosative DNA damage which is related to the activation of Nrf2 and inhibition of NF-κB pathways [ 35 ]. Contrary results were found by Colombo et al 2018 [ 51 ], where 1 mM melatonin induced NF-κB protein expression in HepG2 cells [ 51 ].…”

Melatonin down-regulates microRNA-10a and decreases invasion and migration of triple-negative breast cancer cells

“…In addition, we observed the action of melatonin in decreasing vimentin and claudin 7 proteins, and increasing E-cadherin. According to the literature, this molecule regulates the proliferation of mammary tumor cells, angiogenesis-promoting proteins, and reduces breast cancer tumors in xenographic model (37)(38)(39). Melatonin also acts in metastatic control (22) and decreases the ability of tumor cells to invade and migrate (40).…”