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

Mol Carcinog. 2015 Oct;54(10):1096-109. doi: 10.1002/mc.22179. Epub 2014 May 17.

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 <2 mm, (P = 0.05); 94% reduction in tumors 2-4 mm, (P = 0.001), and 100% 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.

Keywords: AMP-activated protein kinase; berberine; colorectal cancer treatment; mammalian target of rapamycin; prevention; proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Apoptosis / drug effects
  • Azoxymethane / pharmacology
  • Berberine / pharmacology*
  • Carcinogenesis / drug effects*
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Colon / drug effects*
  • Colon / metabolism
  • Colon / pathology
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / metabolism
  • Cyclin D1 / metabolism
  • Cyclooxygenase 2 / metabolism
  • Female
  • HCT116 Cells
  • Humans
  • Mice
  • NF-kappa B / metabolism
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction / drug effects*
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • eIF-2 Kinase / metabolism

Substances

  • NF-kappa B
  • Tumor Suppressor Protein p53
  • Berberine
  • Cyclin D1
  • Cyclooxygenase 2
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Protein-Serine-Threonine Kinases
  • eIF-2 Kinase
  • AMP-Activated Protein Kinases
  • Caspase 3
  • Azoxymethane