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Blood, 15 January 2007, Vol. 109, No. 2, pp. 560-565.
Prepublished online as a Blood First Edition Paper on September 21, 2006; DOI 10.1182/blood-2006-06-029934.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Solenopsin, the alkaloidal component of the fire ant (Solenopsis invicta), is a naturally occurring inhibitor of phosphatidylinositol-3-kinase signaling and angiogenesis
Jack L. Arbiser1,,
Tweeny Kau2,
Martha Konar3,
Krishna Narra4,
Ramani Ramchandran3,
Scott A. Summers4,
Chris J. Vlahos5,
Keqiang Ye6,
Betsy N. Perry1,
William Matter5,
Anthony Fischl5,
James Cook5,
Pamela A. Silver2,
Jenny Bain7,
Philip Cohen7,
David Whitmire8,
Scott Furness8,
Baskaran Govindarajan1, and
J. Phillip Bowen9
1 Department of Dermatology, Emory University School of Medicine, Atlanta, GA;
2 Department of Systems Biology, Harvard Medical School and Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA;
3 Laboratory of Pathology, National Cancer Institute, National Institutes of Health (NIH), Rockville, MD;
4 Department of Internal Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Salt Lake City;
5 Lilly Research Laboratories, Indianapolis, IN;
6 Department of Biochemistry, Emory University School of Medicine, Atlanta, GA; Medical Research Council Protein Phosphorylation Unit,
7 College of Life Sciences University of Dundee, Scotland;
8 Department of Chemistry, University of Georgia, Athens;
9 Department of Chemistry and Biochemistry, University of North Carolina at Greensboro
Phosphatidylinositol-3-kinase (PI3K), and its downstream effector Akt, or protein kinase B (PKB), play a major regulatory role in control of apoptosis, proliferation, and angiogenesis. PI3K and Akt are amplified or overexpressed in a number of malignancies, including sarcomas, ovarian cancer, multiple myeloma, and melanoma. This pathway regulates production of the potent angiogenic factor vascular endothelial growth factor (VEGF), and protects tumor cells against both chemotherapy and reactive oxygen–induced apoptosis through phosphorylation of substrates such as apoptotic peptidase–activating factor-1 (APAF-1), forkhead proteins, and caspase 9. Given its diverse actions, compounds that suppress the PI3K/Akt pathway have potential pharmacologic utility as angiogenesis inhibitors and antineoplastic agents. Using the SVR angiogenesis assay, a screen of natural products, we isolated the alkaloid solenopsin, and found that it is a potent angiogenesis inhibitor. We also found that solenopsin inhibits the PI3K signaling pathway in cells upstream of PI3K, which may underlie its affects on angiogenesis. Consistent with inhibition of the activation of PI3K, solenopsin prevented the phosphorylation of Akt and the phosphorylation of its substrate forkhead box 01a (FOXO1a), a member of the forkhead family of transcription factors. Interestingly, solenopsin also inhibited Akt-1 activity in an ATP-competitive manner in vitro without affecting 27 of 28 other protein kinases tested.
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[Abstract]
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