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

Autor(es)

Chuffa, Luiz Gustavo A. ^[1] ; Fioruci-Fontanelli, Beatriz A. ^[1] ; Mendes, Leonardo O. ^[1] ; Ferreira Seiva, Fabio R. ^[2] ; Martinez, Marcelo ^[3] ; Favaro, Wagner J. ^[4] ; Domeniconi, Raquel F. ^[1] ; Pinheiro, Patricia F. F. ^[1] ; dos Santos, Lucilene Delazari ^[5] ; Martinez, Francisco Eduardo ^[3]

Afiliação do(s) autor(es)

^[1] Univ Estadual Paulista, UNESP, Inst Biosci, Dept Anat, Botucatu, SP - Brazil

^[2] State Univ North Parana, Inst Biol, UENP, Bandeirantes, PR - Brazil

^[3] Univ Fed Sao Carlos, UFSCar, Dept Morphol & Pathol, BR-13560 Sao Carlos, SP - Brazil

^[4] Univ Estadual Campinas, Dept Anat Cell Biol & Physiol & Biophys, UNICAMP, Campinas, SP - Brazil

^[5] Univ Estadual Paulista, UNESP, Ctr Study Venoms & Venomous Anim CEVAP, Botucatu, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: BMC CANCER; v. 15, FEB 6 2015.
• Citações Web of Science: 37

Resumo

Background: Toll-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. Methods: To 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 mu g of 7,12-dimethylbenz(a) anthracene (DMBA) dissolved in 10 mu L 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 mu g/100 g b.w./day) for 60 days. Results: Although 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 (IkB alpha), IkB kinase alpha (IKK-alpha), TNF receptor-associated factor 6 (TRAF6), TRIF, interferon regulatory factor 3 (IRF3), interferon beta (IFN-beta), tumor necrosis factor alpha (TNF-alpha), and interleukin (IL)-6. In addition, mel significantly attenuated the expression of IkB alpha, NFkB p65, TRIF and IRF-3, which are involved in TLR4-mediated signaling in OC during ethanol intake. Conclusion: Collectively, our results suggest that mel attenuates the TLR4-induced MyD88- and TRIF-dependent signaling pathways in ethanol-preferring rats with OC. (AU)

• Processo FAPESP: 11/19294-9 - Indução tumoral ovariana e influência da melatonina sobre o processo inflamatório via sinalização mediada pelo receptor Toll-like 4 em ratas UChB
• Beneficiário: Luiz Gustavo de Almeida Chuffa
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 13/02466-7 - Indução tumoral ovariana e influência da melatonina sobre o processo inflamatório via sinalização mediada pelo receptor Toll-like 4 em ratas UChB
• Beneficiário: Luiz Gustavo de Almeida Chuffa
• Modalidade de apoio: Auxílio à Pesquisa - Regular