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

Toxicol Appl Pharmacol. 2019 Oct 1:380:114696. doi: 10.1016/j.taap.2019.114696. Epub 2019 Aug 2.

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 TGFβ type I receptor induced Smad phosphorylation and EMT markers, whereas ectopic expression of TGFβ 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 could activate lipid raft pathway and modulate TGFβ mediated metastasis, implicating the potential application of TA as a modulator of tumor microenvironment in HCC.

Keywords: Hepatocellular Carcinoma; Lipid Raft; Metastasis; TGFβ; Tolfenamic Acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition
  • Female
  • Humans
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Membrane Microdomains / drug effects*
  • Mice, Inbred BALB C
  • Mice, Nude
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction / drug effects
  • Transforming Growth Factor beta / metabolism*
  • Tumor Microenvironment / drug effects
  • ortho-Aminobenzoates / pharmacology*
  • ortho-Aminobenzoates / therapeutic use

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Antineoplastic Agents
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • ortho-Aminobenzoates
  • tolfenamic acid