Lectin BS-I inhibits cell migration and invasion via AKT/GSK-3β/β-catenin pathway in hepatocellular carcinoma

J Cell Mol Med. 2018 Jan;22(1):315-329. doi: 10.1111/jcmm.13320. Epub 2017 Sep 18.

Abstract

Hepatocellular carcinoma (HCC) is most common malignant cancer worldwide; however, the mortality rate of HCC remains high due to the invasion and metastasis of HCC. Thus, exploring novel treatments to prevent the invasion of HCC is needed for improving clinical outcome of this fatal disease. In this study, we identified lectin from Bandeiraea simplicifolia seeds (BS-I) binds to metastasis-associated HCC cell surface glycans by a lectin microarray and inhibits HCC cell migration and invasion through downregulating the matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9) and urokinase-type plasminogen activator (uPA) production. These effects of BS-I were mediated by inhibiting the activation of AKT/GSK-3β/β-catenin pathway and depended on specificity of lectin BS-I binding to GalNAc. GSK3β inhibitors rescued BS-I-mediated inhibition of migration and invasion of HCC cell. Further, we identified that lectin BS-I interacts with sGrp78, affects membrane localization of sGrp78 and attenuates the binding of sGrp78 and p85 to inhibit the activation of AKT/GSK-3β/β-catenin pathway. Overexpression of Grp78 or P85 rescues BS-I-mediated inhibition of migration and invasion of HCC cell. These findings demonstrated for the first time that BS-I can act as a novel potential drug to prevent the invasion of HCC.

Keywords: AKT/GSK-3β/β-catenin pathway; GRP78; Glycosylation; hepatocellular carcinoma; lectin microarray.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylgalactosamine / metabolism
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology*
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Glycogen Synthase Kinase 3 beta / metabolism*
  • Heat-Shock Proteins / metabolism
  • Humans
  • Lectins / pharmacology*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology*
  • Membrane Glycoproteins / metabolism
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / drug effects*
  • beta Catenin / metabolism*

Substances

  • Heat-Shock Proteins
  • Lectins
  • Membrane Glycoproteins
  • beta Catenin
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Acetylgalactosamine
  • molecular chaperone GRP78