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Published on: March 11, 2014
Down-regulation of human papillomavirus E6/E7 oncogene by arsenic trioxide in cervical carcinoma cells
Soo-Jong Um1, So-Young Lee, Eun-Joo Kim
1Department of Bioscience and Biotechnology/Institute of Bioscience, Sejong University, Seoul 143-747, South Korea.
Abstract:
Arsenic trioxide (As2O3) has been implicated as a promising anticancer agent for treatment of many cancers including acute promylocytic leukemia. However, the molecular mechanisms are not yet fully defined in solid tumor cells, especially cervical cancer cells carrying human papillomavirus (HPV) genome. To analyze detailed mechanisms in vitro, we treated As2O3 to transformed HeLa cells, a well-studied cervical cancer cell line carrying HPV-18 sequence, and investigated its antiproliferative, antiviral and antimetastatic effects. As2O3 reduced survival and growth of HeLa cells in a dose- and time-dependent manner. Several indicatives of apoptosis were demonstrated by DNA fragmentation assay, DAPI nuclear staining and FACS analysis, respectively. Protein levels of p53 and cleavage of poly(ADP)-ribose polymerase were increased in a dose-dependent manner following treatment of As2O3. In parallel, semi-quantitative reverse transcription-polymerase chain reaction showed that the treatment inhibited HPV-18 E6/E7 viral gene expression in HeLa cells. Using transient transfection and CAT ELISA, we also found that AP-1 sites, located proximal to HPV-18 upstream regulatory region (URR) promoter, could be the major target sites for As2O3. Furthermore, As2O3-treated HeLa cells showed lesser capacity of invasion than those of untreated cells by in vitro invasion assay. Taken together, we proposed that antiviral effect, i.e. down-regulation of HPV E6/E7 oncogenes through targeting for AP-1 sites located in HPV URR might be associated with antiproliferative effect, i.e. induction of apoptosis as be resulted from the accumulation of p53, and that antimetastatic effect could be due to the targeted inactivation of AP-1, a transcription factor required for the expression of MMP-1 and -3. Therefore, our finding may provide a logical basis for the development of a new agent treating HPV-associated cervical neoplasia.
Insights
Arsenic trioxide (As2O3) inhibits cervical cancer cell growth by inducing apoptosis and down-regulating human papillomavirus (HPV) E6/E7 oncogenes. This study reveals As2O3
Area of Science:
- Oncology
- Molecular Biology
- Virology
Background:
- Arsenic trioxide (As2O3) shows promise as an anticancer agent, but its mechanisms in solid tumors, particularly HPV-associated cervical cancer, require further elucidation.
- Cervical cancer is frequently driven by the human papillomavirus (HPV) genome, necessitating targeted therapeutic strategies.
Purpose of the Study:
- To investigate the antiproliferative, antiviral, and antimetastatic effects of As2O3 in HPV-18-positive cervical cancer (HeLa) cells.
- To elucidate the molecular mechanisms underlying As2O3's action in this context.
Main Methods:
- HeLa cells were treated with As2O3, followed by assays for cell survival, apoptosis (DNA fragmentation, DAPI staining, FACS), and protein expression (p53, PARP cleavage).
- HPV-18 E6/E7 gene expression was analyzed using semi-quantitative reverse transcription-polymerase chain reaction.
- Transient transfection and CAT ELISA were employed to identify As2O3's interaction with HPV-18 regulatory elements, specifically AP-1 sites.
- In vitro invasion assays assessed the antimetastatic potential of As2O3.
Main Results:
- As2O3 demonstrated dose- and time-dependent inhibition of HeLa cell survival and growth, inducing apoptosis.
- Increased levels of p53 and cleaved PARP indicated activation of apoptotic pathways.
- As2O3 treatment significantly suppressed HPV-18 E6/E7 viral gene expression.
- AP-1 sites within the HPV-18 upstream regulatory region (URR) were identified as key targets for As2O3.
- As2O3-treated cells exhibited reduced invasive capacity, suggesting antimetastatic activity.
Conclusions:
- As2O3 exerts antiproliferative effects in cervical cancer cells, partly through apoptosis induction linked to p53 accumulation.
- The antiviral activity of As2O3, involving the downregulation of HPV E6/E7 oncogenes via AP-1 site targeting, may contribute to its antiproliferative effects.
- Targeting AP-1 transcription factor by As2O3 may also underlie its antimetastatic effects by inhibiting MMP expression, providing a rationale for its use in HPV-associated cervical neoplasia.
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