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.
Bibliographical noteFunding Information:
This study was supported by the NRF (National Research Foundation of Korea) Grant funded by the Korean Government ( NRF-2017R1C1B2008617, NRF-2017M3A9B6061511 and NRF-2018-Fostering Core Leaders of the Future Basic Science Program/Global Ph.D. Fellowship Program) .
© 2021 The Authors
All Science Journal Classification (ASJC) codes
- Cancer Research