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Research Articles: Therapeutics, Targets, and Development

Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt–dependent matrix metalloproteinase-9 expression

¹ Department of Cell Biology, Harvard Medical School, Boston, Massachusetts; ² Natural Medicines Research Center and ³ Molecular Bioprocess Research Center, Korea Research Institute of Bioscience and Biotechnology; and ⁴ Department of Biological Sciences, Korea Advances Institute of Science and Technology, Daejeon, Korea

Requests for reprints: Sang-Oh Yoon, Department of Cell Biology, Harvard Medical School, LHRRB 606, 240 Longwood Avenue, Boston, MA 02115. Phone: 617-432-1281; Fax: 617-432-1144. E-mail: sang-oh_yoon{at}hms.harvard.edu or An-Sik Chung, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea. Phone: 82-42-869-2625; Fax: 82-42-869-2610. E-mail: aschung{at}kaist.ac.kr

Abstract

Matrix metalloproteinase (MMP)-9 plays a key role in tumor invasion. Inhibitors of MMP-9 were screened from Metasequoia glyptostroboides (Dawn redwood) and one potent inhibitor, isoginkgetin, a biflavonoid, was identified. Noncytotoxic levels of isoginkgetin decreased MMP-9 production profoundly, but up-regulated the level of tissue inhibitor of metalloproteinase (TIMP)-1, an inhibitor of MMP-9, in HT1080 human fibrosarcoma cells. The major mechanism of Ras-dependent MMP-9 production in HT1080 cells was phosphatidylinositol 3-kinase (PI3K)/Akt/nuclear factor-B (NF-B) activation. Expression of dominant-active H-Ras and p85 (a subunit of PI3K) increased MMP-9 activity, whereas dominant-negative forms of these molecules decreased the level of MMP-9. H-Ras did not increase MMP-9 in the presence of a PI3K inhibitor, LY294002, and a NF-B inhibitor, SN50. Further studies showed that isoginkgetin regulated MMP-9 production via PI3K/Akt/NF-B pathway, as evidenced by the findings that isoginkgetin inhibited activities of both Akt and NF-B. PI3K/Akt is a well-known key pathway for cell invasion, and isoginkgetin inhibited HT1080 tumor cell invasion substantially. Isoginkgetin was also quite effective in inhibiting the activities of Akt and MMP-9 in MDA-MB-231 breast carcinomas and B16F10 melanoma. Moreover, isoginkgetin treatment resulted in marked decrease in invasion of these cells. In summary, PI3K/Akt is a major pathway for MMP-9 expression and isoginkgetin markedly decreased MMP-9 expression and invasion through inhibition of this pathway. This suggests that isoginkgetin could be a potential candidate as a therapeutic agent against tumor invasion. [Mol Cancer Ther 2006;5(11):2666–75]

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⁵ Unpublished data..

Received 5/31/06; revised 8/15/06; accepted 9/11/06.