Tumor necrosis factor-alpha is a critical pro-inflammatory cytokine produced by macrophages and was once considered an anti-tumor agent. However, a low dose of tumor necrosis factor-alpha can cause epithelial mesenchymal transition, angiogenesis and metastasis. NF-κΒ contributes to epithelial mesenchymal transition induced by tumor necrosis factor-alpha. Kanglaite, an extract from the Coix lacryma-jobi (adlay) seed, is an NF-κΒ inhibitor. The aim of this study was to investigate whether Kanglaite could inhibit epithelial mesenchymal transition caused by tumor necrosis factor-alpha using four colorectal cancer cell lines, HCT106, HCT116, LoVo and CT26. Our results showed that tumor necrosis factor-alpha -mediated activation of NF-κΒ, caused changes in epithelial mesenchymal transition -related protein expression, and increased migration and invasion in all four cell lines. However, these effects were inhibited by Kanglaite when used in combination with tumor necrosis factor-alpha. In a subcutaneous tumor model of CT26, tumor necrosis factor-alpha enhanced the tumorigenic ability of the cells, and again this was inhibited by Kanglaite. However, treatment with Kanglaite alone caused almost no inhibition of epithelial mesenchymal transition -mediated tumor growth, when cells were pretreated with tumor necrosis factor-alpha prior to injection. These results suggest that Kanglaite inhibits tumor necrosis factor-alpha -mediated epithelial mesenchymal transition in colorectal cancer cell lines via inhibition of NF-κΒ.
Paclitaxel is a widely used chemotherapy drug, but development of resistance leads to treatment failure. Tumor cells that are treated with a sublethal dose of paclitaxel for a long period of time show the epithelial‐mesenchymal transition (EMT) phenotype, which leads to metastasis and resistance. All‐trans retinoic acid (ATRA) is always used in combination with paclitaxel and can reverse EMT in many types of cancer cells. The ability of ATRA to reverse EMT in chemoresistant cells is still unknown. In the present study, the ability of ATRA to reverse EMT in paclitaxel‐resistant cells was investigated. Three colorectal cancer cell lines, HCT116, LoVo and CT26, were treated with sublethal doses of paclitaxel to create resistant cell lines. Western blotting, immunocytochemistry, and “parachute” dye‐coupling assays showed that ATRA reverses EMT, inhibits nuclear factor kappa B (NF‐κΒ), and upregulates gap junctions in paclitaxel‐resistant cells. Scratch wound‐healing and Transwell assays showed that ATRA decreases the migration and invasion abilities of paclitaxel‐resistant cells. In addition, the CT26 cell line was used in the Balb/c pulmonary metastasis model to show that ATRA reduces metastasis of paclitaxel‐resistant cells in vivo. Given these data, ATRA may reverse EMT by inhibiting NF‐κΒ and upregulating gap junctions in paclitaxel‐resistant cells.
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