UDP-glucose ceramide glucosyltransferase activates AKT, promoted proliferation, and doxorubicin resistance in breast cancer cells

Cell Mol Life Sci. 2018 Sep;75(18):3393-3410. doi: 10.1007/s00018-018-2799-7. Epub 2018 Mar 17.

Abstract

The UDP-glucose ceramide glucosyltransferase (UGCG) is a key enzyme in the synthesis of glycosylated sphingolipids, since this enzyme generates the precursor for all complex glycosphingolipids (GSL), the GlcCer. The UGCG has been associated with several cancer-related processes such as maintaining cancer stem cell properties or multidrug resistance induction. The precise mechanisms underlying these processes are unknown. Here, we investigated the molecular mechanisms occurring after UGCG overexpression in breast cancer cells. We observed alterations of several cellular properties such as morphological changes, which enhanced proliferation and doxorubicin resistance in UGCG overexpressing MCF-7 cells. These cellular effects seem to be mediated by an altered composition of glycosphingolipid-enriched microdomains (GEMs), especially an accumulation of globotriaosylceramide (Gb3) and glucosylceramide (GlcCer), which leads to an activation of Akt and ERK1/2. The induction of the Akt and ERK1/2 signaling pathway results in an increased gene expression of multidrug resistance protein 1 (MDR1) and anti-apoptotic genes and a decrease of pro-apoptotic gene expression. Inhibition of the protein kinase C (PKC) and phosphoinositide 3 kinase (PI3K) reduced MDR1 gene expression. This study discloses how changes in UGCG expression impact several cellular signaling pathways in breast cancer cells resulting in enhanced proliferation and multidrug resistance.

Keywords: Apoptotic; Glucosylceramide; Glycosphingolipid-enriched microdomains; Glycosphingolipids; MDR1; Multidrug resistance.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Apoptosis / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Proliferation*
  • Cholesterol / analysis
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm* / genetics
  • Female
  • Glucosyltransferases / genetics
  • Glucosyltransferases / metabolism*
  • Humans
  • MCF-7 Cells
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / genetics
  • Sphingolipids / analysis
  • Sphingolipids / metabolism
  • Sphingomyelin Phosphodiesterase / genetics
  • Sphingomyelin Phosphodiesterase / metabolism
  • Sphingosine N-Acyltransferase / genetics
  • Sphingosine N-Acyltransferase / metabolism

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Phosphoinositide-3 Kinase Inhibitors
  • Sphingolipids
  • Doxorubicin
  • Cholesterol
  • Sphingosine N-Acyltransferase
  • Glucosyltransferases
  • ceramide glucosyltransferase
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase C
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Sphingomyelin Phosphodiesterase