Silibinin inhibits cell invasion through inactivation of both PI3K-Akt and MAPK signaling pathways.
Silibinin, isolated from Silybum marianum, has been known for its hepatoprotective properties and recent studies have revealed its antiproliferative and apoptotic effects on several cancer cells. An inhibitory effect of silibinin on tumor invasion and matrix metalloproteinase-2 (MMP-2) and urokinasetype plasminogen activator (u-PA) activities in culture medium has been observed in our previous study and the impacts of silibinin on enzyme activities of MMPs, u-PA, mitogen-activated protein kinase (MAPK) and Akt in A549 cells were continued to explore in this study. Our results showed that silibinin exerted an inhibitory effect on the phosphorylation of Akt, as well as extracellular signal-regulated kinases 1 and 2 (ERK1/2), which are the members of the MAPK family involved in the up-regulation of MMPs or u-PA, while no effects on the activities of p38(MAPK) and stress-activated protein kinase/c-Jun N-terminal kinase were observed. A treatment with silibinin to A549 cells also led to a dose-dependent inhibition on the activation of NF-kappaB, c-Jun and c-Fos. Additionally, the treatment of inhibitors specific for MEK (U0126) or PI3K (LY294002) to A549 cells could result in a reduced expression of MMP-2 and u-PA concomitantly with a marked inhibition on cell invasion. These findings suggested that the inhibition on MMP-2 and u-PA expression by silibinin may be through a suppression on ERK1/2 or Akt phosphorylation, which in turn led to the reduced invasiness of the cancer cells.
Chen
Pei-Ni
PN
Institute of Biochemistry, Chung Shan Medical University, No. 110, Section 1, Chien Kuo N. Road, Taichung 402, Taiwan.
Hsieh
Yih-Shou
YS
Chiou
Hui-Ling
HL
Chu
Shu-Chen
SC
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020944:Silybum marianum / Q000737:chemistry*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D010936:Plant Extracts / Q000494:pharmacology; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D016588:Anticarcinogenic Agents; D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D009025:Morpholines; D009570:Nitriles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010936:Plant Extracts; D012838:Silymarin; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000077385:Silybin; D020928:Mitogen-Activated Protein Kinases; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2