title: Berberine modulates AP-1 activity to suppress HPV transcription and downstream signaling to induce growth arrest and apoptosis in cervical cancer cells.
abstract: BACKGROUND
  Specific types of high risk Human papillomaviruses (HR-HPVs) particularly, HPV types 16 and 18 cause cervical cancer and while the two recently developed vaccines against these HPV types are prophylactic in nature, therapeutic options for treatment and management of already existing HPV infection are not available as yet. Because transcription factor, Activator Protein-1 (AP-1) plays a central role in HPV-mediated cervical carcinogenesis, we explored the possibility of its therapeutic targeting by berberine, a natural alkaloid derived from a medicinal plant species, Berberis which has been shown to possess anti-inflammatory and anti-cancer properties with no known toxicity; however, the effect of berberine against HPV has not been elucidated.
  
  
  RESULTS
  We studied the effect of berberine on HPV16-positive cervical cancer cell line, SiHa and HPV18-positive cervical cancer cell line, HeLa using electrophoretic mobility gel shift assays, western and northern blotting which showed that berberine could selectively inhibit constitutively activated AP-1 in a dose- and time-dependent manner and downregulates HPV oncogenes expression. Inhibition of AP-1 was also accompanied by changes in the composition of their DNA-binding complex. Berberine specifically downregulated expression of oncogenic c-Fos which was also absent in the AP-1 binding complex. Treatment with berberine resulted in repression of E6 and E7 levels and concomitant increase in p53 and Rb expression in both cell types. Berberine also suppressed expression of telomerase protein, hTERT, which translated into growth inhibition of cervical cancer cells. Interestingly, a higher concentration of berberine was found to reduce the cell viability through mitochondria-mediated pathway and induce apoptosis by activating caspase-3.
  
  
  CONCLUSIONS
  These results indicate that berberine can effectively target both the host and viral factors responsible for development of cervical cancer through inhibition of AP-1 and blocking viral oncoproteins E6 and E7 expression. Inhibition of AP-1 activity by berberine may be one of the mechanisms responsible for the anti-HPV effect of berberine. We propose that berberine is a potentially promising compound for the treatment of cervical cancer infected with HPV.
authors.affiliation: Division of Molecular Oncology, Institute of Cytology and Preventive Oncology (Indian Council of Medical Research), I-7, Sector-39, Noida, Gautam Budh Nagar - 201301 India.
authors.forename: Sutapa
authors.initials: S
authors.lastname: Mahata
authors.forename: Alok C
authors.initials: AC
authors.lastname: Bharti
authors.forename: Shirish
authors.initials: S
authors.lastname: Shukla
authors.forename: Abhishek
authors.initials: A
authors.lastname: Tyagi
authors.forename: Syed A
authors.initials: SA
authors.lastname: Husain
authors.forename: Bhudev C
authors.initials: BC
authors.lastname: Das
mesh_terms: D052685:Alphapapillomavirus / Q000187:drug effects / Q000235:genetics; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001599:Berberine / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D002583:Uterine Cervical Neoplasms
chemical_list: D000970:Antineoplastic Agents; D009856:Oncogene Proteins, Viral; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D016160:Retinoblastoma Protein; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53; D001599:Berberine; D019098:Telomerase