Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt-dependent matrix metalloproteinase-9 expression.
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-kappaB (NF-kappaB) 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-kappaB inhibitor, SN50. Further studies showed that isoginkgetin regulated MMP-9 production via PI3K/Akt/NF-kappaB pathway, as evidenced by the findings that isoginkgetin inhibited activities of both Akt and NF-kappaB. 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.
Yoon
Sang-Oh
SO
Department of Cell Biology, Harvard Medical School, LHRRB 606, 240 Longwood Avenue, Boston, MA 02115, USA. sang-oh_yoon@hms.harvard.edu
Shin
Sejeong
S
Lee
Ho-Jae
HJ
Chun
Hyo-Kon
HK
Chung
An-Sik
AS
D044946:Biflavonoids / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005354:Fibrosarcoma / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000097782:NF-kappaB-Inducing Kinase
D044946:Biflavonoids; D005419:Flavonoids; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019715:Tissue Inhibitor of Metalloproteinase-1; D000097782:NF-kappaB-Inducing Kinase; C452984:isoginkgetin