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

• Published in: Molecular cancer therapeutics 2006-11, Vol.5 (11), p.2666-2675
• Main Authors: Yoon, Sang-Oh, Shin, Sejeong, Lee, Ho-Jae, Chun, Hyo-Kon, Chung, An-Sik
• Format: Article
• Language: English
• Subjects: Biflavonoids - pharmacology; Breast Neoplasms - metabolism; Dose-Response Relationship, Drug; Female; Fibrosarcoma - metabolism; Flavonoids - pharmacology; Humans; Isoginkgetin; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase Inhibitors; MMP-9; Neoplasm Invasiveness; Neoplasms - enzymology; NF-kappaB-Inducing Kinase; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors; PI3K/Akt; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Tumor Cells, Cultured; tumor invasion
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-06-0321

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 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]