Document Detail


Constitutive activation of transcription factor AP-1 in cervical cancer and suppression of human papillomavirus (HPV) transcription and AP-1 activity in HeLa cells by curcumin.
MedLine Citation:
PMID:  15514944     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The transcription factor AP-1 plays a central role in the transcriptional regulation of specific types of high-risk human papillomaviruses (HPVs) such as HPV16 and HPV18, which are etiologically associated with the development of cancer of the uterine cervix in women. In our study, we investigated the AP-1 binding activity and the expression pattern of different members of the AP-1 transcription factor family (c-Jun, JunB, JunD, c-Fos, FosB, Fra-1 and Fra-2) in different grades of cervical lesions starting from mild dysplasia to invasive cervical tumors, including normal control tissues, using specific antibodies raised against each of the AP-1 members. Results indicate that though AP-1 showed high binding activity and the majority of its members were highly expressed in tumor tissues, there is a distinct pattern of gradual increase of c-fos and a concomitant decrease of fra-1 expression that perfectly match the progression of cervical lesions. While c-fos is highly expressed in invasive cervical tumor, the expression of fra-1 becomes almost nil or absent, but the reverse is true in both controls and early precancerous lesions. These findings corroborate the results obtained in the cervical cancer cell line, HeLa. Interestingly, despite very low or absent AP-1 binding in normal as well as in premalignant lesions, AP-1 transcription and its binding activity was found to be very high in malignant tissues showing a preferential heterodimerization of c-fos with JunB instead of its canonical dimerization partner c-jun. Both in vivo and in vitro studies demonstrate that the overexpression of c-fos and downregulation of fra-1 expression as well as a change in the dimerization pattern of the AP-1 complex seem to play a crucial role during progression to malignancy. In a previous study, we demonstrated that a synthetic antioxidant, pyrrolidine dithiocarbamate (PDTC) can selectively downregulate HPV expression in human keratinocytes and cervical cancer cell lines. Since a redox regulatory pathway is involved in the expression of HPV that can be modulated by an antioxidant-induced reconstitution of the AP-1 transcription complex, we have used curcumin (diferuloylmethane), an active component of the perennial herb turmeric, which is a potent antioxidant and is well-known for its antiinflammatory and anticarcinogenic activity, to modulate the transcription of AP-1 and HPV. We demonstrate for the first time that curcumin can selectively downregulate HPV18 transcription as well as the AP-1 binding activity in HeLa cells. Most interestingly, curcumin can reverse the expression dynamics of c-fos and fra-1 in this tumorigenic cell line, mimicking the expression pattern observed in normal controls or precancerous lesions. Observation of curcumin-mediated complete downregulation of AP-1 binding activity and reversal of c-fos/fra-1 transcription to a normal state in tumorigenic HeLa cells represents a novel mechanism that can control transcription of pathogenic HPVs during keratinocyte differentiation and progression of cervical cancer. Our study thus provides a basis for developing a novel therapeutic approach to control pathogenic HPV infection by using potent antioxidative agents, such as curcumin.
Authors:
Bhupesh K Prusty; Bhudev C Das
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  113     ISSN:  0020-7136     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2005 Mar 
Date Detail:
Created Date:  2004-12-27     Completed Date:  2005-03-07     Revised Date:  2007-07-24    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  951-60     Citation Subset:  IM    
Copyright Information:
(c) 2004 Wiley-Liss, Inc.
Affiliation:
Division of Molecular Oncology, Institute of Cytology & Preventive Oncology (Indian Council of Medical Research), Maulana Azad Medical College Campus, New Delhi, India.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology
Base Sequence
Curcumin / pharmacology*
DNA Primers
Female
Hela Cells
Humans
Nucleic Acid Hybridization
Papillomaviridae / drug effects,  genetics*
Polymerase Chain Reaction / methods
Transcription Factor AP-1 / drug effects,  genetics*,  metabolism
Transcription, Genetic / drug effects*
Uterine Cervical Neoplasms / genetics*,  virology
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/DNA Primers; 0/Transcription Factor AP-1; 458-37-7/Curcumin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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