Melatonin‐mediated Bim up‐regulation and cyclooxygenase‐2 (COX‐2) down‐regulation enhances tunicamycin‐induced apoptosis in MDA‐MB‐231 cells

Abstract

Melatonin is involved in many physiological functions, and it has differential effects on apoptosis in normal and cancer cells. However, the mechanism of its antitumor roles is not well understood. In this study, we show that melatonin enhances tunicamycin-induced apoptosis in human breast carcinoma MDA-MB-231 cells. Melatonin up-regulates pro-apoptotic protein Bim expression at the transcriptional levels in the presence of tunicamycin. Melatonin inhibits tunicamycin-induced COX-2 expression in MDA-MB-231 cells. Furthermore, inhibition of COX-2 activity using the COX-2 inhibitor, NS398, increases tunicamycin-induced apoptosis. Interestingly, these effects were not associated with melatonin receptor signal pathways. Pertussis toxin (a general Gi protein inhibitor) or luzindole (a nonspecific melatonin receptor antagonist) did not reverse the effect of melatonin. In addition, melatonin blocked tunicamycin-induced NF-κB transcriptional activity, p65 nuclear translocation, and p38 MAPK activation. Melatonin-mediated p38 MAPK inhibition contributed to decreased COX-2 mRNA stability. Taken together, our results suggest that melatonin enhances antitumor function through up-regulation of Bim expression and down-regulation of COX-2 expression in tunicamycin-treated MDA-MB-231 cells.

Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis

“…The disruption of nocturnal rise in melatonin production and secretion due to excessive light exposure during the normal dark period, i.e., light pollution, has long been known to correlate with a higher cancer risk [175,176,177,178,179,180]. Any alteration in the nocturnal rise in circulating melatonin, however, is unavoidably also accompanied by a general perturbation of circadian rhythms, which are a result of malfunction of the activity of the master biological clock, the suprachiasmatic nucleus (SCN).…”

Melatonin as a potential anticarcinogen for non-small-cell lung cancer

“…Melatonin exerts anti-apoptotic effects in normal cells exposed to toxic agents or metabolic injury. However, melatonin usually has the opposite effect on cancer cells and induces apoptosis in a wide range of different tumors (e.g., breast, prostate, cervix, liver, colon, pancreas, kidney, neuro) [18, 20, 24, 25, 28, 75–78]; thus, the induction of apoptosis of cancer cells (but not of normal cells) is one of the mechanisms by which melatonin limits tumor growth [61, 79–88]. This specifically relates to lung cancer given that melatonin treatment dose- and time- dependent decreased the viability of human A549 and PC9 lung adenocarcinoma cells, and increased their apoptotic index.…”

Melatonin-Induced Oncostasis, Mechanisms and Clinical Relevance

“…Melatonin upregulates FOXO3a-mediated activation of the proapoptotic protein Bim and enhances endoplasmic reticulum stressinduced apoptosis through inhibition of COX-2 expression and reduction of Bcl-2 levels, and by an elevation of the pro-apoptotic transcription factor C/EBP homologous protein (CHOP). Woo et al demonstrated that melatonin has an antitumor function through down-regulation of COX-2 expression by inhibition of NF-κB and p38 MAPK activation [62]. Therefore, the stimulatory effects of melatonin on apoptosis in cancer cells involve both the intrinsic and the extrinsic apoptotic pathways [6].…”