title: Berberine, a natural compound, suppresses Hedgehog signaling pathway activity and cancer growth.
abstract: BACKGROUND
  Berberine (BBR), a natural alkaloid compound, is used as a non-prescription drug in China for treating diarrhea and gastroenteritis. Many studies have revealed that BBR possesses anticancer effect. However, the molecular mechanisms underlying its anticancer action is far from being fully elucidated. This study is aimed to determine the effect of BBR on the hedgehog (Hh) activity and the growth of cancers addiction to Hh activity.
  
  
  METHODS
  The Hh activity was determined by dual luciferase assays and quantitative RT-PCR analyses. The growth inhibition of BBR on medulloblastoma which was obtained from ptch+/-;p53-/- mice was analyzed by 5-bromo-2-deoxyuridine (Brdu) assays and by allografting the medulloblastoma into nude mice. The data were statistically analyzed by one-way analysis of variance (ANOVA), and multiple comparison between the groups was performed using Dunnett's method.
  
  
  RESULTS
  In this study, we found that BBR significantly inhibited the Hh pathway activity. Meanwhile, we observed that BBR failed to affect the transcriptional factors activities provoked by tumor necrosis factor-α (TNF-α) and Prostaglandin E2 (PGE2), thus suggesting its unique property against Hh pathway activity. Further studies revealed that BBR inhibited the Hh pathway activity by potentially targeting the critical component Smoothened (Smo) and most likely shared the same binding site on Smo with cyclopamine, a classical Smo inhibitor. Finally, we demonstrated that BBR obviously suppressed the Hh-dependent medulloblastoma growth in vitro and in vivo.
  
  
  CONCLUSIONS
  Collectively, our study uncovered a novel molecular mechanism responsible for the anticancer action of BBR, thus opening the way for the usage of BBR for therapeutics of cancers addiction to aberrant Hh pathway activity.
authors: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, P.R. China. 13211030033@fudan.edu.cn.
authors: Juan
authors: J
authors: Wang
authors: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, P.R. China. 12211030033@fudan.edu.cn.
authors: Yuanqiu
authors: Y
authors: Peng
authors: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, P.R. China. 12211030031@fudan.edu.cn.
authors: Yuan
authors: Y
authors: Liu
authors: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, P.R. China. 14211030042@fudan.edu.cn.
authors: Jun
authors: J
authors: Yang
authors: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Rd, Shanghai, 201203, P.R. China. dingning@fudan.edu.cn.|State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. dingning@fudan.edu.cn.
authors: Ning
authors: N
authors: Ding
authors: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, P.R. China. wftan@fudan.edu.cn.
authors: Wenfu
authors: W
authors: Tan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001599:Berberine / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008527:Medulloblastoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000072086:Smoothened Receptor
chemical_list: D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D001599:Berberine