Rosmarinic acid represses colitis-associated colon cancer: A pivotal involvement of the TLR4-mediated NF-κB-STAT3 axis

Previously, we found that rosmarinic acid (RA) exerted anti-inflammatory activities in a dextran sulfate sodium (DSS)-induced colitis model. Here, we investigated the anti-tumor effects of RA on colitis-associated colon cancer (CAC) and the underlying molecular mechanisms. We established an azoxymet...

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Vydáno v:	Neoplasia (New York, N.Y.) Ročník 23; číslo 6; s. 561 - 573
Hlavní autoři:	Jin, Bo-Ram, Chung, Kyung-Sook, Hwang, Soonjae, Hwang, Sam Noh, Rhee, Ki-Jong, Lee, Minho, An, Hyo-Jin
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Elsevier Inc 01.06.2021 Neoplasia Press Elsevier
Témata:	Animals Biomarkers Cell Line, Tumor Cinnamates - chemistry Cinnamates - pharmacology Colitis-associated colon cancer (CAC) Colitis-Associated Neoplasms - drug therapy Colitis-Associated Neoplasms - etiology Colitis-Associated Neoplasms - metabolism Colitis-Associated Neoplasms - pathology Colonic Neoplasms - drug therapy Colonic Neoplasms - etiology Colonic Neoplasms - metabolism Colonic Neoplasms - pathology Depsides - chemistry Depsides - pharmacology Disease Models, Animal Humans Immunohistochemistry Male Mice Models, Molecular Myeloid differentiation factor 2 (MD-2) NF-kappa B - metabolism Nuclear factor-kappa B (NF-κB) Original Research Rosmarinic Acid Rosmarinic acid (RA) Signal transducer and activator of transcription 3 (STAT3) Signal Transduction - drug effects STAT3 Transcription Factor - metabolism Structure-Activity Relationship Toll-Like Receptor 4 - metabolism Toll-like receptor-4 (TLR4) Xenograft Model Antitumor Assays CAC Rosmarinic acid (RA) DSS IHC CPT STAT3 Myeloid differentiation factor 2 (MD-2) IBD Toll-like receptor-4 (TLR4) UC Colitis-associated colon cancer (CAC) RA Signal transducer and activator of transcription 3 (STAT3) NF-κB CRC Nuclear factor-kappa B (NF-κB) TLR4 AOM
ISSN:	1476-5586, 1522-8002, 1476-5586
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Shrnutí:	Previously, we found that rosmarinic acid (RA) exerted anti-inflammatory activities in a dextran sulfate sodium (DSS)-induced colitis model. Here, we investigated the anti-tumor effects of RA on colitis-associated colon cancer (CAC) and the underlying molecular mechanisms. We established an azoxymethane (AOM)/DSS-induced CAC murine model for in vivo studies and used a conditioned media (CM) culture system in vitro. H&E staining, immunohistochemistry, western blot assay, enzyme-linked immunosorbent assay, molecular docking, co-immunoprecipitation, and immunofluorescence assay were utilized to investigate how RA prevented colorectal cancer. In the AOM/DSS-induced CAC murine model, RA significantly reduced colitis severity, inflammation-related protein expression, tumor incidence, and colorectal adenoma development. It significantly modulated toll-like receptor-4 (TLR4)-mediated nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) activation, thus attenuating the expression of anti-apoptotic factors, which mediate transcription factor-dependent tumor growth. In vitro, RA inhibited CM-induced TLR4 overexpression and competitively inhibited TLR4-myeloid differentiation factor 2 complex in an inflammatory microenvironment. Thus, RA suppressed NF-κB and STAT3 activation in colon cancer cells in an inflammatory microenvironment. Therefore, RA suppressed colitis-associated tumorigenesis in the AOM/DSS-induced CAC murine model and abrogated human colon cancer progression in an inflammatory microenvironment by propitiating TLR4-mediated NF-κB and STAT3 activation, pleiotropically.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work
ISSN:	1476-5586 1522-8002 1476-5586
DOI:	10.1016/j.neo.2021.05.002