Resveratrol Chemosensitizes TNF-β-Induced Survival of 5-FU-Treated Colorectal Cancer Cells
AbstractObjective: Resveratrol, a safe and multitargeted natural agent, has been linked with inhibition of survival and invasion of tumor cells. Tumor Necrosis Factor-β (TNF-β) (Lymphotoxin α) is known as an inflammatory cytokine, however, the underlying mechanisms for its pro-carcinogenic effects and whether resveratrol can suppress these effects in the tumor microenvironment are poorly understood. Methods: We investigated whether resveratrol modulates the effects of 5-Fluorouracil (5-FU) and TNF-β on the malignant potential of human colorectal cancer (CRC) cells (HCT116) and their corresponding isogenic 5-FU-chemoresistant derived clones (HCT116R) in 3D-alginate tumor microenvironment. Results: CRC cells cultured in alginate were able to migrate from alginate and the numbers of migrated cells were significantly increased in the presence of TNF-β, similar to TNF-α, and dramatically decreased by resveratrol. We found that TNF-β promoted chemoresistance in CRC cells to 5-FU compared to control cultures and resveratrol chemosensitizes TNF-β-induced increased capacity for survival and invasion of HCT116 and HCT116R cells to 5-FU. Furthermore, TNF-β induced a more pronounced cancer stem cell-like (CSC) phenotype (CD133, CD44, ALDH1) and resveratrol suppressed formation of CSC cells in two different CRC cells and this was accompanied with a significant increase in apoptosis (caspase-3). It is noteworthy that resveratrol strongly suppressed TNF-β-induced activation of tumor-promoting factors (NF-κB, MMP-9, CXCR4) and epithelial-to-mesenchymal-transition-factors (increased vimentin and slug, decreased E-cadherin) in CRC cells. Conclusion: Our results clearly demonstrate for the first time that resveratrol modulates the TNF-β signaling pathway, induces apoptosis, suppresses NF-κB activation, epithelial-to-mesenchymal-transition (EMT), CSCs formation and chemosensitizes CRC cells to 5-FU in a tumor microenvironment. View Full-Text
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Buhrmann, C.; Yazdi, M.; Popper, B.; Shayan, P.; Goel, A.; Aggarwal, B.B.; Shakibaei, M. Resveratrol Chemosensitizes TNF-β-Induced Survival of 5-FU-Treated Colorectal Cancer Cells. Nutrients 2018, 10, 888.
Buhrmann C, Yazdi M, Popper B, Shayan P, Goel A, Aggarwal BB, Shakibaei M. Resveratrol Chemosensitizes TNF-β-Induced Survival of 5-FU-Treated Colorectal Cancer Cells. Nutrients. 2018; 10(7):888.Chicago/Turabian Style
Buhrmann, Constanze; Yazdi, Mina; Popper, Bastian; Shayan, Parviz; Goel, Ajay; Aggarwal, Bharat B.; Shakibaei, Mehdi. 2018. "Resveratrol Chemosensitizes TNF-β-Induced Survival of 5-FU-Treated Colorectal Cancer Cells." Nutrients 10, no. 7: 888.
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