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First published on June 27, 2006; DOI: 10.1124/mol.106.025809

0026-895X/06/7003-1143-1149$20.00
Mol Pharmacol 70:1143-1149, 2006

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A Naphthoquinone Derivative, Shikonin, Has Insulin-Like Actions by Inhibiting Both Phosphatase and Tensin Homolog Deleted on Chromosome 10 and Tyrosine Phosphatases

Kiyomi Nigorikawa, Kyoko Yoshikawa, Tomo Sasaki, Eiji Iida, Mariko Tsukamoto, Hitomi Murakami, Tomohiko Maehama, Kaoru Hazeki, and Osamu Hazeki

Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan (K.N., K.Y., T.S., E.I., M.T., H.M., K.H., O.H.); and Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan (T.M.)

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 µM. 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.

Received for publication April 16, 2006.

Accepted for publication June 27, 2006.

Address correspondence to: Dr. Osamu Hazeki, Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima 734-8553, Japan. E-mail: hazeki{at}hiroshima-u.ac.jp




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S.-C. Chiu and N.-S. Yang
Inhibition of Tumor Necrosis Factor-{alpha} through Selective Blockade of Pre-mRNA Splicing by Shikonin
Mol. Pharmacol., June 1, 2007; 71(6): 1640 - 1645.
[Abstract] [Full Text] [PDF]


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