title: A naphthoquinone derivative, shikonin, has insulin-like actions by inhibiting both phosphatase and tensin homolog deleted on chromosome 10 and tyrosine phosphatases.
abstract: The 1,4-naphthoquinone derivative, shikonin, has been shown to increase glucose uptake by adipocytes and myocytes with minor effects on protein tyrosine phosphorylation in the cells (Biochem Biophys Res Commun 292:642-651, 2002). The present study was performed to examine the mechanism of this action of shikonin. Shikonin inhibited the phosphatidylinositol 3,4,5-triphosphate (PtdIns-3,4,5-P3) phosphatase activity of recombinant phosphatase and tensin homolog deleted on chromosome 10 (PTEN) with an IC50 value of 2.7 microM. Shikonin induced marked accumulation of PtdIns-3,4,5-P3 and activation of protein kinase B (PKB) in Chinese hamster ovary cells expressing insulin receptors. In addition to its effect on PTEN, shikonin was found to inhibit several protein phosphatases in cell-free systems. Its effect on tyrosine phosphorylation in intact cells was far weaker than that of pervanadate, a widely used tyrosine phosphatase inhibitor, despite the observation that the effect of shikonin on PKB was more potent than that of pervanadate. These results suggested that the inhibition of PTEN provides a clue to its potent insulin-like actions. We also found that naphthoquinones, including 1,2-naphthoquinone, inhibit PTEN in the cell-free system, which suggested that the effect on PTEN (and thus the effect on phosphatidylinositol 3-kinase signaling) should be taken into account when examining the pharmacological actions of naphthoquinone derivatives.
authors.affiliation: Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Nigorikawa
authors.forename: Kyoko
authors.initials: K
authors.lastname: Yoshikawa
authors.forename: Tomo
authors.initials: T
authors.lastname: Sasaki
authors.forename: Eiji
authors.initials: E
authors.lastname: Iida
authors.forename: Mariko
authors.initials: M
authors.lastname: Tsukamoto
authors.forename: Hitomi
authors.initials: H
authors.lastname: Murakami
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Maehama
authors.forename: Kaoru
authors.initials: K
authors.lastname: Hazeki
authors.forename: Osamu
authors.initials: O
authors.lastname: Hazeki
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D007328:Insulin / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology*; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism
chemical_list: D007328:Insulin; D009285:Naphthoquinones; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; C016101:shikonin; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase