title: Induction of Glycosphingolipid GM3 Expression by Valproic Acid Suppresses Cancer Cell Growth.
abstract: Glycosphingolipid GM3, a known suppressor of epidermal growth factor receptor (EGFR) phosphorylation, inhibits cell proliferation. Valproic acid, conversely, is known as an up-regulator of GM3 synthase gene (ST3GAL5). To test the possibility that valproic acid could inhibit EGFR phosphorylation by increasing the level of GM3 in cells, we treated A431 epidermoid carcinoma cells with valproic acid and found that valproic acid treatment caused an about 6-fold increase in the GM3 level but only a marginal increase in the GM2 level in these cells and that the observed increase in GM3 level was valproic acid dose-dependent. Consistent with this observation, valproic acid treatment induced GM3 synthase gene expression by about 8-fold. Furthermore, phosphorylation of EGFR was reduced, and cell proliferation was inhibited following valproic acid treatment. Consistent with these results, transient expression of GM3 synthase gene in A431 cells also increased cellular level of GM3, reduced phosphorylation of EGFR, and inhibited cell proliferation. Treatment with l-phenyl-2-decanoylamino-3-morpholino-l-propanol, an inhibitor of glucosylceramide synthesis, decreased the cellular level of GM3 and reduced the inhibitory effects of valproic acid on EGFR phosphorylation and cell proliferation. These results suggested that induction of GM3 synthesis was enough to inhibit proliferation of cancer cells by suppressing EGFR activity. Valproic acid treatment similarly increased the GM3 level and reduced phosphorylation of EGFR in U87MG glioma cells and inhibited their proliferation. These results suggested that up-regulators of GM3 synthase gene, such as valproic acid, are potential suppressors of cancer cell proliferation.
authors.affiliation: From the Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Sapporo 062-8517, Japan.|Division of Biomembrane Research Institute, Pacific Northwest Research Institute, Seattle, Washington 98122, and.
authors.forename: Nagako
authors.initials: N
authors.lastname: Kawashima
authors.affiliation: From the Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Sapporo 062-8517, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Nishimiya
authors.affiliation: From the Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Sapporo 062-8517, Japan.
authors.forename: Shouta
authors.initials: S
authors.lastname: Takahata
authors.affiliation: From the Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Sapporo 062-8517, Japan, k-nakayama@aist.go.jp.|Research Institute for Sustainable Chemistry, National Institute of Advanced Industrial Science and Technology (AIST), Hiroshima 739-0046, Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Nakayama
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005679:G(M3) Ganglioside / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D012799:Sialyltransferases / Q000096:biosynthesis* / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D005679:G(M3) Ganglioside; D025521:Tumor Suppressor Proteins; D014635:Valproic Acid; D012799:Sialyltransferases; C021343:haematoside synthetase; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: GM3; cell proliferation; epidermal growth factor receptor (EGFR); ganglioside; glycolipid; glycosphingolipid; histone deacetylase inhibitor (HDAC inhibitor) (HDI); valproic acid