Galangin enhances TGF-β1-mediated growth inhibition by suppressing phosphorylation of threonine 179 residue in Smad3 linker region

Biochem Biophys Res Commun. 2017 Dec 16;494(3-4):706-713. doi: 10.1016/j.bbrc.2017.10.138. Epub 2017 Oct 31.

Abstract

Smad3 linker phosphorylation is a candidate target for several kinases that play important roles in cancer cell initiation, proliferation and progression. Also, Smad3 is an essential intracellular mediator of TGF-β1-induced transcriptional responses during carcinogenesis. Therefore, it is highly advantageous to identify and develop inhibitors targeting Smad3 linker phosphorylation for the treatment of cancers. Galangin (3,5,7-trihydroxyflavone) has been known to be an active flavonoid showing a cytotoxic effect on several cancer cells. However, the mechanism of action of galangin in various cancers remains unclear, and there has been no report concerning regulation of Smad3 phosphorylation by galangin. In the present study, we show that galangin significantly induced apoptosis and inhibited cell proliferation in the presence of TGF-β1 in both human prostate and pancreatic cancer cell lines. Particularly, galangin effectively inhibits phosphorylation of the Thr-179 site at Smad3 linker region through suppression of CDK4 phosphorylation. Thus, galangin can be a promising candidate as a selective inhibitor to suppress phosphorylation of Smad3 linker region.

Keywords: Galangin; Pancreatic cancer; Prostate cancer; Smad3 linker phosphorylation; TGF-β1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Apoptosis / drug effects
  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Flavonoids / administration & dosage*
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Phosphorylation / drug effects
  • Protein Binding
  • Smad3 Protein / metabolism*
  • Threonine / metabolism
  • Transforming Growth Factor beta1 / metabolism*
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Flavonoids
  • SMAD3 protein, human
  • Smad3 Protein
  • Transforming Growth Factor beta1
  • galangin
  • Threonine