Berberine regulates AMP-activated protein kinase signaling pathways and inhibits colon tumorigenesis in mice.
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.
Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland.|Oncology Department, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
Weidong
W
Li
Oncology Department, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
Baojin
B
Hua
Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
Shakir M
SM
Saud
Oncology Department, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
Hongsheng
H
Lin
Oncology Department, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
Wei
W
Hou
Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Matthias S
MS
Matter
Office of Cancer Complementary and Alternative Medicine, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Rockville, Maryland.
Libin
L
Jia
Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
Nancy H
NH
Colburn
Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
Matthew R
MR
Young
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001397:Azoxymethane / Q000494:pharmacology; D001599:Berberine / Q000494:pharmacology*; D063646:Carcinogenesis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D001599:Berberine; D019938:Cyclin D1; D051546:Cyclooxygenase 2; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D019892:eIF-2 Kinase; D055372:AMP-Activated Protein Kinases; D053148:Caspase 3; D001397:Azoxymethane
AMP-activated protein kinase; berberine; colorectal cancer treatment; mammalian target of rapamycin; prevention; proliferation