Berberine modulates AP-1 activity to suppress HPV transcription and downstream signaling to induce growth arrest and apoptosis in cervical cancer cells

Molecular Cancer

Research

Syed A Husain¹  Abhishek Tyagi²  Shirish Shukla²  Alok C Bharti²  Sutapa Mahata²  Bhudev C Das³ 

[1] Department of Biosciences, Faculty of Natural Sciences, Jamia Millia Islamia, 110025, New Delhi, India;Division of Molecular Oncology, Institute of Cytology and Preventive Oncology (Indian Council of Medical Research), I-7, Sector-39, Gautam Budh Nagar, 201301, Noida, India;Division of Molecular Oncology, Institute of Cytology and Preventive Oncology (Indian Council of Medical Research), I-7, Sector-39, Gautam Budh Nagar, 201301, Noida, India;Dr. B.R Ambedkar Centre for Biomedical Research, University of Delhi (North Campus), 110007, Delhi, India;

关键词: Cervical Cancer;    Berberine;    Electrophoretic Mobility Shift Assay;    Cervical Cancer Cell;    SiHa Cell;   

DOI  :  10.1186/1476-4598-10-39

 received in 2010-08-10, accepted in 2011-04-15,  发布年份 2011

来源: Springer

【 摘 要 】

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.Conclusion-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.

【 授权许可】

Unknown   
© Mahata et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.