sp2 -Iminosugar α-glucosidase inhibitor 1-C-octyl-2-oxa-3-oxocastanospermine specifically affected breast cancer cell migration through Stim1, β1-integrin, and FAK signaling pathways

J Cell Physiol. 2017 Dec;232(12):3631-3640. doi: 10.1002/jcp.25832. Epub 2017 Apr 25.

Abstract

Aberrant glycosylation changes on many glycoproteins are often related to cancer progression and metastasis. sp2 -Iminosugar-type castanospermine analogues, inhibitors of α-glucosidases, have been reported to exhibit antitumor activity. However, their effects on cell migration and the underlying molecular mechanism are not fully understood. Here, we investigated the effect of the pseudo-C-octyl glycoside 2-oxa-3-oxocastanospermine derivatives (CO-OCS) on breast cancer cells (MCF-7 and MDA-MB-231 cells), and MCF-10A mammary normal cell lines. We showed that CO-OCS treatment results in the drastic decrease of breast cancer cell migration without affecting cell proliferation. Furthermore, CO-OCS significantly reduced both the expression of β1-integrin, which is a crucial interacting partner of Focal Adhesion Kinase (FAK), and the phosphorylation rates of FAK and ERK1/2. CO-OCS also drastically reduced Ca2+ entry through Store Operated Channels (SOC). Orai1 and Stim1, two N-glycosylated proteins, are involved in Store-Operated Calcium Entry (SOCE), and are essential for breast tumor cell migration. Our results showed that CO-OCS decreased the expression, at the protein level, of Stim1 without affecting that of Orai1. Moreover, cell migration and SOCE were attenuated by CO-OCS as well as when Stim1 was silenced. In contrast, in MCF-10A cells, CO-OCS slightly reduced cell migration, but was without effect on gene expression of Stim1, Orai1, β1-integrin, or FAK and ERK1/2 activation. Our results provide strong evidence for a significant effect of CO-OCS on breast cancer cell migration and support that this effect was associated with β1-integrin, Stim1, and FAK signaling pathways.

Keywords: Stim1 and Orai1; breast cancer; calcium; glycosylation; migration.

MeSH terms

  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Movement / drug effects*
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Focal Adhesion Kinase 1 / metabolism*
  • Glycoside Hydrolase Inhibitors / pharmacology*
  • Glycosylation
  • Humans
  • Indolizines / pharmacokinetics*
  • Integrin beta1 / metabolism*
  • MCF-7 Cells
  • Neoplasm Invasiveness
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Protein Processing, Post-Translational / drug effects
  • RNA Interference
  • Signal Transduction / drug effects
  • Stromal Interaction Molecule 1 / genetics
  • Stromal Interaction Molecule 1 / metabolism*
  • Time Factors
  • Transfection

Substances

  • 1-C-octyl-2-oxa-3-oxocastanospermine
  • Glycoside Hydrolase Inhibitors
  • Indolizines
  • Integrin beta1
  • Neoplasm Proteins
  • STIM1 protein, human
  • Stromal Interaction Molecule 1
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • Extracellular Signal-Regulated MAP Kinases