Bufalin inhibits migration and invasion in human hepatocellular carcinoma SK-Hep1 cells through the inhibitions of NF-kB and matrix metalloproteinase-2/-9-signaling pathways.
Metastasis plays an important role in mortality of cancer patients. Migration and invasion are the major characteristics of tumor metastasis. The induction of matrix metalloproteinases (MMPs) such as MMP-2 and -9 are particularly important for the invasiveness of various cancer cells. Bufalin, a class of toxic steroids, was purified from the skin glands of Bufo gargarizans or Bufo melanostictus; it is known to inhibit proliferation of human cancer cells. In this study, we investigated the antiinvasive mechanisms of bufalin in the human hepatocellular cancer cell line SK-Hep1. Bufalin significantly reduced serum-induced cell invasion and migration. Furthermore, bufalin markedly inhibited MMP-2 and -9 activity, mRNA expression and protein levels in SK-Hep1 cells. Bufalin attenuated phosphoinisitide-3-kinase (PI3K) and phosphorylation of AKT which was associated with reduced levels of nuclear factor kappa B (NF-κB). Bufalin also suppressed protein levels of FAK and Rho A, VEGF, MEKK3, MKK7, and uPA and it diminished NF-κB translocation. Based on these observations, we propose that bufalin is acts as an antiinvasive agent by inhibiting MMP-2 and -9 and involving PI3K/AKT and NF-κB pathways. Bufalin is a potential therapeutic agent that may have efficacy in preventing the invasion and metastasis of malignant liver tumors.
Department of Chinese-Western Medicine Integration, Chung Shan Medical University Hospital, Taichung, 402, Taiwan, ROC; School of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan, ROC.
Ya-Yin
YY
Chen
Hsu-Feng
HF
Lu
Shu-Chun
SC
Hsu
Chao-Lin
CL
Kuo
Shu-Jen
SJ
Chang
Jen-Jyh
JJ
Lin
Ping-Ping
PP
Wu
Jia-You
JY
Liu
Ching-Hsiao
CH
Lee
Jing-Gung
JG
Chung
Jin-Biou
JB
Chang
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002018:Bufanolides / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009361:Neoplasm Invasiveness; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D002018:Bufanolides; D016328:NF-kappa B; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C022777:bufalin
NF-κB; SK-Hep1; bufalin; matrix metalloproteinase-2/-9; migration