Berberine regulates AMP‐activated protein kinase signaling pathways and inhibits colon tumorigenesis in mice

Citations Over TimeTop 10% of 2014 papers

Abstract

Colorectal cancer, a leading cause of cancer death, has been linked to inflammation and obesity. Berberine, an isoquinoline alkaloid, possesses anti-inflammatory, anti-diabetes and anti-tumor properties. In the azoxymethane initiated and dextran sulfate sodium (AOM/DSS) promoted colorectal carcinogenesis mouse model, berberine treated mice showed a 60% reduction in tumor number (P = 0.009), a 48% reduction in tumors 4 mm (P = 0.02) compared to vehicle treated mice. Berberine also decreased AOM/DSS induced Ki-67 and COX-2 expression. In vitro analysis showed that in addition to its anti-proliferation activity, berberine also induced apoptosis in colorectal cancer cell lines. Berberine activated AMP-activated protein kinase (AMPK), a major regulator of metabolic pathways, and inhibited mammalian target of rapamycin (mTOR), a downstream target of AMPK. Furthermore, 4E-binding protein-1 and p70 ribosomal S6 kinases, downstream targets of mTOR, were down regulated by berberine treatment. Berberine did not affect Liver kinase B1 (LKB1) activity or the mitogen-activated protein kinase pathway. Berberine inhibited Nuclear Factor kappa-B (NF-κB) activity, reduced the expression of cyclin D1 and survivin, induced phosphorylation of p53 and increased caspase-3 cleavage in vitro. Berberine inhibition of mTOR activity and p53 phosphorylation was found to be AMPK dependent, while inhibition NF-κB was AMPK independent. In vivo, berberine also activated AMPK, inhibited mTOR and p65 phosphorylation and activated caspase-3 cleavage. Our data suggests that berberine suppresses colon epithelial proliferation and tumorigenesis via AMPK dependent inhibition of mTOR activity and AMPK independent inhibition of NF-κB.

Related Papers

• → Thienopyridone Drugs Are Selective Activators of AMP-Activated Protein Kinase β1-Containing Complexes(2008)250 cited
• → Homogenous Fluorescent Assays for Characterizing Small-Molecule Activators of AMP-Activated Protein Kinase (AMPK)(2008)2 cited
• New findings in AMP-activated protein kinase(2014)
• 돌외 추출물로부터 순수 분리된 saponin 계열의 화합물인 Damulin B에 의한 AMP-activated protein kinase (AMPK)의 활성화 기작에 대한 연구(2011)
• Coptidis Rhizoma Water Extract Stimulates 5＇-AMP-Activated Protein Kinase in Rat Skeletal Muscle(2011)