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Ruthenium oligonucleotides, targeting HPV16 E6 oncogene, inhibit the growth of cervical cancer cells under illumination by a mechanism involving p53

Gene Therapy volume 20, pages 435–443 (2013)Cite this article

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Abstract

High-risk Human Papillomaviruses (HPV) has been found to be associated with carcinomas of the cervix, penis, vulva/vagina, anus, mouth and oro-pharynx. As the main tumorigenic effects of the HPV have been attributed to the expression of E6 and E7 genes, different gene therapy approaches have been directed to block their expression such as antisense oligonucleotides (ASO), ribozymes and small interfering RNAs. In order to develop a gene-specific therapy for HPV-related cancers, we investigated a potential therapeutic strategy of gene silencing activated under illumination. Our aim according to this antisense therapy consisted in regulating the HPV16 E6 oncogene by using an E6-ASO derivatized with a polyazaaromatic ruthenium (RuII) complex (E6-Ru-ASO) able, under visible illumination, to crosslink irreversibly the targeted sequence. We examined the effects of E6-Ru-ASO on the expression of E6 and on the cell growth of cervical cancer cells. We demonstrated using HPV16+ SiHa cervical cancer cells that E6-Ru-ASO induces after illumination, a reactivation of p53, the most important target of E6, as well as the inhibition of cell proliferation with a selective repression of E6 at the protein level. These results suggest that E6-Ru ASOs, activated under illumination and specifically targeting E6, are capable of inhibiting HPV16+ cervical cancer cell proliferation.

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Acknowledgements

The research presented here was supported by the Walloon Region (CARCINOM Waleo-2 project). LM thanks the FNRS for a fellowship (‘aspirant’ at the FNRS). The authors are grateful to a NanoBio programme (Grenoble) for the facilities of the Synthesis platform.

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Authors and Affiliations

  1. GIGA-Cancer, Laboratory of Experimental Pathology, University of Liège, Liège, Belgium

    A Reschner, P Hubert & P Delvenne

  2. GIGA-Research, Laboratory of Virology and Immunology, University of Liège, Liège, Belgium

    S Bontems & J Piette

  3. Organic Chemistry and Photochemistry, Université libre de Bruxelles (ULB), Bruxelles, Belgium

    S Le Gac, J Lambermont, L Marcélis, C Moucheron & A Kirsch-De Mesmaeker

  4. Département de chimie moléculaire, UMR CNRS 5250, Université Joseph Fourier, Grenoble, France

    E Defrancq

  5. Research Unit of Cell Biology (URBC)-NARILIS, University of Namur (FUNDP), Namur, Belgium

    M Raes

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Reschner, A., Bontems, S., Le Gac, S. et al. Ruthenium oligonucleotides, targeting HPV16 E6 oncogene, inhibit the growth of cervical cancer cells under illumination by a mechanism involving p53. Gene Ther 20, 435–443 (2013). https://doi.org/10.1038/gt.2012.54

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