PMID- 24838344 OWN - NLM STAT- MEDLINE DCOM- 20151207 LR - 20211203 IS - 1098-2744 (Electronic) IS - 0899-1987 (Print) IS - 0899-1987 (Linking) VI - 54 IP - 10 DP - 2015 Oct TI - Berberine regulates AMP-activated protein kinase signaling pathways and inhibits colon tumorigenesis in mice. PG - 1096-109 LID - 10.1002/mc.22179 [doi] AB - 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-kappaB) 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-kappaB 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-kappaB. CI - (c) 2014 Wiley Periodicals, Inc. FAU - Li, Weidong AU - Li W AD - Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland. AD - Oncology Department, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China. FAU - Hua, Baojin AU - Hua B AD - Oncology Department, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China. FAU - Saud, Shakir M AU - Saud SM AD - Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland. FAU - Lin, Hongsheng AU - Lin H AD - Oncology Department, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China. FAU - Hou, Wei AU - Hou W AD - Oncology Department, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China. FAU - Matter, Matthias S AU - Matter MS AD - Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. FAU - Jia, Libin AU - Jia L AD - Office of Cancer Complementary and Alternative Medicine, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Rockville, Maryland. FAU - Colburn, Nancy H AU - Colburn NH AD - Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland. FAU - Young, Matthew R AU - Young MR AD - Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland. LA - eng GR - Z99 CA999999/Intramural NIH HHS/United States GR - ZIA BC011159/Intramural NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140517 PL - United States TA - Mol Carcinog JT - Molecular carcinogenesis JID - 8811105 RN - 0 (NF-kappa B) RN - 0 (Tumor Suppressor Protein p53) RN - 0I8Y3P32UF (Berberine) RN - 136601-57-5 (Cyclin D1) RN - EC 1.14.99.1 (Cyclooxygenase 2) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.1 (eIF-2 Kinase) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - EC 3.4.22.- (Caspase 3) RN - MO0N1J0SEN (Azoxymethane) SB - IM MH - AMP-Activated Protein Kinases/*metabolism MH - Animals MH - Apoptosis/drug effects MH - Azoxymethane/pharmacology MH - Berberine/*pharmacology MH - Carcinogenesis/*drug effects/metabolism/pathology MH - Caspase 3/metabolism MH - Cell Line, Tumor MH - Colon/*drug effects/metabolism/pathology MH - Colorectal Neoplasms/*drug therapy/metabolism MH - Cyclin D1/metabolism MH - Cyclooxygenase 2/metabolism MH - Female MH - HCT116 Cells MH - Humans MH - Mice MH - NF-kappa B/metabolism MH - Phosphorylation/drug effects MH - Protein Serine-Threonine Kinases/metabolism MH - Signal Transduction/*drug effects MH - TOR Serine-Threonine Kinases/metabolism MH - Tumor Suppressor Protein p53/metabolism MH - eIF-2 Kinase/metabolism PMC - PMC4504840 MID - NIHMS643545 OTO - NOTNLM OT - AMP-activated protein kinase OT - berberine OT - colorectal cancer treatment OT - mammalian target of rapamycin OT - prevention OT - proliferation EDAT- 2014/05/20 06:00 MHDA- 2015/12/15 06:00 PMCR- 2016/10/01 CRDT- 2014/05/20 06:00 PHST- 2013/11/07 00:00 [received] PHST- 2014/02/12 00:00 [revised] PHST- 2014/04/16 00:00 [accepted] PHST- 2014/05/20 06:00 [entrez] PHST- 2014/05/20 06:00 [pubmed] PHST- 2015/12/15 06:00 [medline] PHST- 2016/10/01 00:00 [pmc-release] AID - 10.1002/mc.22179 [doi] PST - ppublish SO - Mol Carcinog. 2015 Oct;54(10):1096-109. doi: 10.1002/mc.22179. Epub 2014 May 17.