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

Abstract

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.

Methylation-mediated repression of microRNA-129-2 suppresses cell aggressiveness by inhibiting high mobility group box 1 in human hepatocellular carcinoma

“…Recent studies of MMPs involvement in tumor metastasis such angiogenesis, migration and invasion have received extensive attention that resulted in amounts of experimental data in favor of critical roles of MMPs in these processes [25–29]. Expectedly, overexpression of miR-129-2 significantly decreased the AKT activity and the expression of phosphorylated AKT, MMP2 and MMP9 in HCC cells ( P < 0.05, Figure 6A).…”

Identification of anti-tumor components from toad venom

“…Bufalin and cardiotonic steroid, isolated from toad venom, were identified to cause apoptosis in human prostate and breast cancer cells by upregulating the expression of caspase family genes in tumor cells (7,8). Bufalin can also suppress cell proliferation and inhibit the migration and invasion of tumor cells, although the molecular mechanisms remain unknown (6,9,10). By contrast, arenobufagin, another major component of toad venom, was reported as a specific inhibitor of VEGF-mediated angiogenesis (6).…”

Preparation of bufalin-loaded pluronic polyetherimide nanoparticles, cellular uptake, distribution, and effect on colorectal cancer

“…[13][14][15] Because of its toxicity, insolubility in water, fast metabolism, short half-life, and other shortcomings, 16 its application in cancer therapy is limited. However, studies have shown that nanocomposites can combine bufalin to overcome these shortcomings.…”