2,3,5,6-Tetramethylpyrazine Targets Epithelial-Mesenchymal Transition by Abrogating Manganese Superoxide Dismutase Expression and TGFβ-Driven Signaling Cascades in Colon Cancer Cells

Biomolecules. 2022 Jun 25;12(7):891. doi: 10.3390/biom12070891.

Abstract

Epithelial-mesenchymal transition (EMT) is a crucial process in which the polarized epithelial cells acquire the properties of mesenchymal cells and gain invasive properties. We have previously demonstrated that manganese superoxide dismutase (MnSOD) can regulate the EMT phenotype by modulating the intracellular reactive oxygen species. In this report, we have demonstrated the EMT-suppressive effects of 2,3,5,6-Tetramethylpyrazine (TMP, an alkaloid isolated from Chuanxiong) in colon cancer cells. TMP suppressed the expression of MnSOD, fibronectin, vimentin, MMP-9, and N-cadherin with a parallel elevation of occludin and E-cadherin in unstimulated and TGFβ-stimulated cells. Functionally, TMP treatment reduced the proliferation, migration, and invasion of colon cancer cells. TMP treatment also modulated constitutive activated as well as TGFβ-stimulated PI3K/Akt/mTOR, Wnt/GSK3/β-catenin, and MAPK signaling pathways. TMP also inhibited the EMT program in the colon cancer cells-transfected with pcDNA3-MnSOD through modulation of MnSOD, EMT-related proteins, and oncogenic pathways. Overall, these data indicated that TMP may inhibit the EMT program through MnSOD-mediated abrogation of multiple signaling events in colon cancer cells.

Keywords: MnSOD; TGFβ signaling; Tetramethylpyrazine; epithelial-mesenchymal transition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Movement
  • Colonic Neoplasms* / drug therapy
  • Colonic Neoplasms* / metabolism
  • Epithelial-Mesenchymal Transition*
  • Glycogen Synthase Kinase 3
  • Humans
  • Phosphatidylinositol 3-Kinases / metabolism
  • Pyrazines
  • Superoxide Dismutase / genetics
  • Transforming Growth Factor beta / metabolism

Substances

  • Pyrazines
  • Transforming Growth Factor beta
  • Superoxide Dismutase
  • Glycogen Synthase Kinase 3
  • tetramethylpyrazine

Grants and funding

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NRF-2021R1I1A2060024 and NRF-2022R1I1A1A01071593). A.P.K. was supported by a grant from the Singapore Ministry of Education (MOE-T2EP30120-0016). H.E. is supported by the National Research Foundation of Singapore (NUS R&G Postdoc Fellowship) (NUS-76).