| Lopinavir up-regulates expression of the antiviral protein ribonuclease L in human papillomavirus-positive cervical carcinoma cells. | |
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MedLine Citation:
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PMID: 21685539 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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BACKGROUND: We have previously shown that the HIV protease inhibitor lopinavir has selective toxicity against human papillomavirus (HPV)-positive cervical carcinoma cells via an unknown mechanism. METHODS: SiHa cervical carcinoma cells were stably transfected with the proteasome sensor vector pZsProSensor-1 to confirm lopinavir inhibits the proteasome in these cells. The Panorama Xpress profiler 725 antibody array was then used to analyse specific changes in protein expression in lopinavir-treated versus control untreated SiHa cells followed by PCR and western blotting. Colorimetric growth assays of lopinavir-treated E6/E7 immortalised versus control human keratinocytes were performed. Targeted small interfering RNA gene silencing followed by growth assay comparison of lopinavir-treated/untreated SiHa cells was also used. RESULTS: Lopinavir induced an increase in the fluorescence of pZsProSensor-1 transfected SiHa cells, indicative of proteasomal inhibition. Ribonuclease L (RNASEL) protein was shown to be up-regulated in lopinavir-treated SiHa cells, which was confirmed by PCR and western blot. Targeted silencing of RNASEL reduced the sensitivity of SiHa cells to lopinavir. Selective toxicity against E6/E7 immortalised keratinocytes versus control cells was also seen with lopinavir and was associated with up-regulated RNASEL expression. CONCLUSIONS: These data are consistent with the toxicity of lopinavir against HPV-positive cervical carcinoma cells being related to its ability to block viral proteasome activation and induce an up-regulation of the antiviral protein RNASEL. This is supported by the drug's selective toxicity and up-regulation of RNASEL in E6/E7 immortalised keratinocytes combined with the increased resistance to lopinavir observed in SiHa cells following silencing of RNASEL gene expression. |
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Authors:
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Gavin Batman; Anthony W Oliver; Ingeborg Zehbe; Christina Richard; Lynne Hampson; Ian N Hampson |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Antiviral therapy Volume: 16 ISSN: 2040-2058 ISO Abbreviation: Antivir. Ther. (Lond.) Publication Date: 2011 |
Date Detail:
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Created Date: 2011-06-20 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9815705 Medline TA: Antivir Ther Country: England |
Other Details:
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Languages: eng Pagination: 515-25 Citation Subset: IM |
Affiliation:
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Gynaecological Oncology Laboratories, School of Cancer & Enabling Sciences, University of Manchester, St Mary's Hospital, Manchester, UK. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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