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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Veröffentlicht in:Neoplasia (New York, N.Y.) Jg. 23; H. 6; S. 561 - 573
Hauptverfasser: Jin, Bo-Ram, Chung, Kyung-Sook, Hwang, Soonjae, Hwang, Sam Noh, Rhee, Ki-Jong, Lee, Minho, An, Hyo-Jin
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Elsevier Inc 01.06.2021
Neoplasia Press
Elsevier
Schlagworte:
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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Zusammenfassung: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.
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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