The involvement of lipid raft pathway in suppression of TGF β-mediated metastasis by tolfenamic acid in hepatocellular carcinoma cells.

The involvement of lipid raft pathway in suppression of TGFβ-mediated metastasis by tolfenamic acid in hepatocellular carcinoma cells. Toxicol Appl Pharmacol. 2019 Aug 02;:114696 Authors: Sun J, Tao R, Mao T, Feng Z, Guo Q, Zhang X Abstract TGFβ signaling plays an important role in orchestrating a favorable microenvironment for tumor cell growth and promoting epithelial-mesenchymal transition. As a conventional nonsteroidal anti-inflammation drugs, tolfenamic acid (TA) has been previously reported to exhibit anti-cancer activity. Herein, we investigated the effect of TA on TGFβ-mediated pro-metastatic activity and the underlying mechanisms in hepatocellular carcinoma (HCC). As a result, TA suppresses TGFβ-induced migration and glycolysis in HCC cells, which is accompanied with reduced Smad phosphorylation and subsequent nuclear transcription activity. Mechanistically, TA promotes lipid raft-caveolar internalization pathway of TGFβ receptor, therefore leading to its rapid turnover. Consistently, TA inhibits constitutively active type I receptor induced Smad phosphorylation and EMT markers, whereas ectopic expression of type II receptor could partially rescue TGFβ-mediated Smad2 phosphorylation and downstream genes expression in the presence of TA. Furthermore, TA inhibited HCC cells invasion in nude mice, associated with the alteration of characteristics related with EMT and glycolysis of cancer cells. Our study suggests TA coul...
Source: Toxicology and Applied Pharmacology - Category: Toxicology Authors: Tags: Toxicol Appl Pharmacol Source Type: research