Melatonin attenuates the TLR4-mediated inflammatory response through MyD88- and TRIF-dependent signaling pathways in an in vivo model of ovarian cancer

Abstract

BackgroundToll-like receptors (TLRs) are effector molecules expressed on the surface of ovarian cancer (OC) cells, but the functions of the TLR2/TLR4 signaling pathways in these cells remain unclear. Melatonin (mel) acts as an anti-inflammatory factor and has been reported to modulate TLRs in some aggressive tumor cell types. Therefore, we investigated OC and the effect of long-term mel therapy on the signaling pathways mediated by TLR2 and TLR4 via myeloid differentiation factor 88 (MyD88) and toll-like receptor-associated activator of interferon (TRIF) in an ethanol-preferring rat model.MethodsTo induce OC, the left ovary of animals either consuming 10% (v/v) ethanol or not was injected directly under the bursa with a single dose of 100 μg of 7,12-dimethylbenz(a)anthracene (DMBA) dissolved in 10 μL of sesame oil. The right ovaries were used as sham-surgery controls. After developing OC, half of the animals received i.p. injections of mel (200 μg/100 g b.w./day) for 60 days.ResultsAlthough mel therapy was unable to reduce TLR2 levels, it was able to suppress the OC-associated increase in the levels of the following proteins: TLR4, MyD88, nuclear factor kappa B (NFkB p65), inhibitor of NFkB alpha (IkBα), IkB kinase alpha (IKK-α), TNF receptor-associated factor 6 (TRAF6), TRIF, interferon regulatory factor 3 (IRF3), interferon β (IFN-β), tumor necrosis factor alpha (TNF-α), and interleukin (IL)-6. In addition, mel significantly attenuated the expression of IkBα, NFkB p65, TRIF and IRF-3, which are involved in TLR4-mediated signaling in OC during ethanol intake.ConclusionCollectively, our results suggest that mel attenuates the TLR4-induced MyD88- and TRIF-dependent signaling pathways in ethanol-preferring rats with OC.

Melatonin reversed tumor necrosis factor‐alpha‐inhibited osteogenesis of human mesenchymal stem cells by stabilizing SMAD1 protein

“…Melatonin is recognized as a novel potential modulator of MSCs differentiation and has been proven to be able to potently promote osteogenesis and osteoblast maturation through several pathways, including MAPK signaling, Wnt/beta‐catenin signaling, and BMP‐SMAD1 signaling . On the other hand, melatonin has also been found to exert anti‐inflammatory actions by downregulating pro‐inflammatory cytokines, scavenging oxygen free radicals, reducing nitric oxide production, and blunting NLRP3 (nucleotide‐binding domain, leucine‐rich repeat containing receptor‐related protein 3) inflammasome activation . Melatonin was shown to be able to suppress TNFα signaling activation in numerous different inflammatory models and also directly decrease TNFα production via several mechanisms, such as PI3K/Akt signaling activation, NF‐κB signaling inhibition, and the scavenging of reactive oxygen species .…”

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

“…In this model, melatonin reduced the frequency of ovarian carcinomas, sarcomas and cystic teratomas, diagnosed on the basis of histological subtype [229]. Subsequent studies confirmed that the molecular events normally associated with this type of experimental ovarian cancers were reversed by melatonin treatment [230,231,232]. Most recently, quantitative profiling of these tumors verified the broad modulatory actions of melatonin on essential signaling pathways in ovarian cancer cells [233] hinting at the possibility that melatonin should be considered as a therapeutic opportunity for women with this deadly disease.…”

Melatonin-Induced Oncostasis, Mechanisms and Clinical Relevance

“…Toll-like receptors activation, via a myeloid differentiation primary response gene 88 (MyD88)-dependent pathway, induces an inflammatory response and promotes activation of the transcription factor NF-κB. The antiproliferative effect of melatonin involves negative regulation of MyD88 [33] and NF-κB [34]. These factors have proliferative effects by direct action on cyclin D1.…”