title: Berberine radiosensitizes human esophageal cancer cells by downregulating homologous recombination repair protein RAD51.
abstract: BACKGROUND
  Esophageal squamous cell carcinomas (ESCC) have poor prognosis. While combined modality of chemotherapy and radiotherapy increases survival, most patients die within five years. Development of agents that confer cancer cell-specific chemo- and radiosensitivity may improve the therapy of ESCC. We here reported the discovery of berberine as a potent radiosensitizing agent on ESCC cells.
  
  
  RESULTS
  Berberine at low concentrations (<15 µM) substantially radiosensitized ESCC cells. X-ray induced DNA double-strand breaks (DSBs) persist longer in ESCC cells pretreated with berberine. Berberine pretreatment led to a significant downregulation of RAD51, a key player in homologous recombination repair, in ESCC cells, but not in non-malignant human cells. Downregulation of RAD51 by RNA interference similarly radiosensitized the cancer cells, and, conversely, introduction of exogenous RAD51 was able to significantly counteract the radiosensitizing effect of berberine, thus establishing RAD51 as a key determinant in radiation sensitivity. We also observed that RAD51 was commonly overexpressed in human ESCC tissues, suggesting that it is necessary to downregulate RAD51 to achieve high radio- or chemotherapeutic efficacy of ESCC in clinic, because overexpression of RAD51 is known to confer radio- and chemoresistance.
  
  
  CONCLUSIONS
  Berberine can effectively downregulate RAD51 in conferring radiosensitivity on esophageal cancer cells. Its clinical application as an adjuvant in chemotherapy and radiotherapy of esophageal cancers should be explored.
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Liu
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
authors.forename: Zhaojian
authors.initials: Z
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Minnan
authors.initials: M
authors.lastname: Zhao
authors.forename: Chunyan
authors.initials: C
authors.lastname: Hao
authors.forename: Shuai
authors.initials: S
authors.lastname: Feng
authors.forename: Haiyang
authors.initials: H
authors.lastname: Guo
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Yang
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
mesh_terms: D001599:Berberine / Q000494:pharmacology*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D059765:Homologous Recombination / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D034622:RNA Interference; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D059767:Recombinational DNA Repair / Q000187:drug effects* / Q000528:radiation effects; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C468783:H2AX protein, human; D006657:Histones; D011838:Radiation-Sensitizing Agents; D001599:Berberine; D051135:Rad51 Recombinase