β1-Integrin plays a major role in resveratrol-mediated anti-invasion effects in the CRC microenvironment

Abstract

Background: Tumor microenvironment (TME) is one of the most important factors in tumor aggressiveness, with an active exchange between tumor and other TME-associated cells that promotes metastasis. The tumor-inhibitory effect of resveratrol on colorectal cancer (CRC) cells has been frequently reported. However, whether resveratrol can specifically suppress TME-induced CRC invasion via β1-integrin receptors has not been fully elucidated yet.Methods: Two CRC cell lines (HCT116, RKO) were cultured in multicellular, pro-inflammatory 3D-alginate TME cultures (containing fibroblasts, T-lymphocytes) to investigate the role of β1-integrin receptors in the anti-invasive and anti-metastatic effect of resveratrol by antisense oligonucleotides (ASO).Results: Our results show that resveratrol dose-dependently suppressed the migration-promoting adhesion adapter protein paxillin and simultaneously enhanced the expression of E-cadherin associated with the phenotype change of CRC cells, and their invasion. Moreover, resveratrol blocked TME-induced phosphorylation and nuclear translocation of p65-NF-κB, which was associated with changes in the expression pattern of epithelial-mesenchymal-transition-related biomarkers (slug, vimentin, E-cadherin), metastasis-related factors (CXCR4, MMP-9, FAK), and apoptosis (caspase-3). Finally, transient transfection of β1-integrin, in contrast to knockdown of NF-κB, abrogated most anti-invasive, anti-metastatic effects as well as downstream signaling of resveratrol, resulting in a concomitant increase in CRC cell invasion, indicating a central role of β1-integrin receptors in the anti-invasive function of resveratrol.Conclusion: These results demonstrate for the first time that silencing β1-integrins may suppress, at least in part the inhibitory effects of resveratrol on invasion and migration of CRC cells, underscoring the crucial homeostatic role of β1-integrin receptors.

Prevention and Co-Management of Breast Cancer-Related Osteoporosis Using Resveratrol

“…By positively regulating the TME, resveratrol has been shown to significantly affect tumorigenesis of BC by various mechanisms, including the induction of apoptosis via p53 signaling [159]. This finding was confirmed for other cancer cell lines such as colorectal cancer (CRC) cells, as evidenced by the reversal of p53 suppression by resveratrol [156]. In this context, a dose-dependent effect pattern of the natural polyphenol was recently confirmed through the inhibition of the NAD-dependent protein deacetylase Sirt-1 and the acetylation of p53 protein at higher resveratrol concentrations [156].…”

“…A majority of the data classify resveratrol as a safe and, in most cases, well-tolerated supplement, depending on the dosage [154]. In fact, the divergence in the functional dichotomy of resveratrol has been observed to affect cells in different ways, with cell survival being increased at low resveratrol concentrations and suppressed at high resveratrol concentrations [155,156].…”

Resveratrol Supplements Reduce the Risk of Aging-Related Cardiac Disease after Cardiorespiratory Fitness

“…IL-6 after binding its gp130 receptor leads to cardiomyocyte hypertrophy, increased fibrosis, and heart failure. In contrast, the JAK/STAT pathway has been elucidated to late essential preconditioning of the cardiorespiratory fitness and cardiac hypertrophy, especially in pathological hypertrophy that proves heart function rupture [22]. The roles of TGF-β1 and MMPs (MMP2 and MMP9) in tissue remodeling are intertwined.…”

Rhodium(III)–Picolinamide Complexes Act as Anticancer and Antimetastasis Agents via Inducing Apoptosis and Autophagy

“…The early step of EMT is the local infiltration of the surrounding extracellular matrix (ECM) and the stromal cell layer . Cancer cells degrade ECMs by concentrating the enzyme activity of matrix metalloproteinases (MMPs) using special F-actin-rich projections, which allows cancer cells to migrate and invade outside the microenvironment. , The EGFR signaling pathway and the integrin signaling pathway are involved in regulating many cellular functions . Focal adhesion kinase (FAK) is one of the most significant downstream effector factors that targets cell adhesion to ECM and mediates downstream signal events of ECM integrin conjugation. , Thus, FAK plays a vital role in cell migration and invasion. , …”