Resveratrol Suppresses Cross-Talk between Colorectal Cancer Cells and Stromal Cells in Multicellular Tumor Microenvironment: A Bridge between In Vitro and In Vivo Tumor Microenvironment Study

Abstract

The interaction between tumor cells and the tumor microenvironment (TME) is an important process for the development of tumor malignancy. Modulation of paracrine cross-talk could be a promising strategy for tumor control within the TME. The exact mechanisms of multi-targeted compound resveratrol are not yet fully understood. Whether resveratrol can modulate paracrine signal transduction-induced malignancy in the multicellular-TME of colorectal cancer cells (CRC) was investigated. An in vitro model with 3D-alginate HCT116 cells in multicellular-TME cultures (fibroblast cells, T-lymphocytes) was used to elucidate the role of TNF-β, Sirt1-ASO and/or resveratrol in the proliferation, invasion and cancer stem cells (CSC) of CRC cells. We found that multicellular-TME, similar to TNF-β-TME, promoted proliferation, colony formation, invasion of CRC cells and enabled activation of CSCs. However, after co-treatment with resveratrol, the malignancy of multicellular-TME reversed to HCT116. In addition, resveratrol reduced the secretion of T-lymphocyte/fibroblast (TNF-β, TGF-β3) proteins, antagonized the T-lymphocyte/fibroblast-promoting NF-κB activation, NF-κB nuclear translocation and thus the expression of NF-κB-promoting biomarkers, associated with proliferation, invasion and survival of CSCs in 3D-alginate cultures of HCT116 cells induced by TNF-β- or multicellular-TME, but not by Sirt1-ASO, indicating the central role of this enzyme in the anti-tumor function of resveratrol. Our results suggest that in vitro multicellular-TME promotes crosstalk between CRC and stromal cells to increase survival, migration of HCT116 and the resveratrol/Sirt1 axis suppresses this loop by modulating paracrine agent secretion and NF-κB signaling. Fibroblasts and T-lymphocytes are promising targets for resveratrol in the prevention of CRC metastasis.

Evidence That Tumor Microenvironment Initiates Epithelial-To-Mesenchymal Transition and Calebin A can Suppress it in Colorectal Cancer Cells

“…To address the role of Calebin A in modulating NF-κB attachment on DNA, we performed a DNA-binding assay with dithiothreitol (DTT) as earlier detailed (Buhrmann et al, 2020a). TME cultures were established and then nuclei and cytoplasm were separated from each other, from CRC cells that remained untreated and/or treated with Calebin A (1, 2, and 5 µM) plus DTT (5 mM) alone or in both for 1 h, as has been thoroughly outlined in previous work (Buhrmann et al, 2020a;Buhrmann et al, 2020b;Buhrmann et al, 2020c). The nuclei were then prepared, separated by SDS-PAGE and blotted as indicated earlier.…”

Curcumin Attenuates Environment-Derived Osteoarthritis by Sox9/NF-kB Signaling Axis

“…Its modulatory effects on inflammatory processes and related diseases, including OA and RA, have also been studied. In previous studies, our group has demonstrated the anabolic and protective effects of curcumin on IL-1β-, TNF-α-, or TNF-β-stimulated chondrocytes, indicating its chondroprotective properties for the treatment of OA and related osteoarticular problems [ 22 , 23 , 24 ]. Thus, NF-kB signaling participates in the pathogenesis of OA, has been identified as one of the most important signaling pathways, and significantly regulates OA-associated inflammatory mediators [ 25 ].…”

Resveratrol and Its Analogs: Potent Agents to Reverse Epithelial-to-Mesenchymal Transition in Tumors

“…Furthermore, over 50% of patients show resistance to 5-FU in the therapeutic course (15). RES has been found to inactive the NF-kB signaling pathway potently in earlier researches (104)(105)(106). The NF-kB signaling pathway not only closely links to inflammation and cancer (107), but also propels the process of EMT and metastasis (17).…”