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Title | Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt-dependent matrix metalloproteinase-9 expression |
| 이소징게틴 PI3K/AKT의존적 MMP-9발현조절에 의한 암세포 침윤억제 |
Authors | S O Yoon; S Shin; Ho Jae Lee; Hyo Kon Chun; A S Chung |
Publisher | Wiley-Blackwell |
Issue Date | 2006 |
Citation | Molecular Cancer Therapeutics, vol. 5, no. 11, pp. 2666-2675 |
Keywords | isoginkgetin; matrix metalloproteinase inhibitor; phosphatidylinositol 3 kinase; protein kinase B; tissue inhibitor of metalloproteinase 1; animal cell; cancer cell culture; cancer invasion; human cell; protein expression |
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-κB (NF-κB) 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-κB inhibitor, SN50. Further studies showed that isoginkgetin regulated MMP-9 production via PI3K/Akt/ NF-κB pathway, as evidenced by the findings that isoginkgetin inhibited activities of both Akt and NF-κB. 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 B16F1O 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. |
ISSN | 1535-7163 |
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Registered Date |
2017-04-19 |
