TY - JOUR
T1 - Ruthenium oligonucleotides, targeting HPV16 E6 oncogene, inhibit the growth of cervical cancer cells under illumination by a mechanism involving p53
AU - Reschner, A.
AU - Bontems, S.
AU - Le Gac, S.
AU - Lambermont, J.
AU - Marcélis, L.
AU - Defrancq, E.
AU - Hubert, P.
AU - Moucheron, C.
AU - Kirsch-De Mesmaeker, A.
AU - Raes, M.
AU - Piette, J.
AU - Delvenne, P.
PY - 2013/4/1
Y1 - 2013/4/1
N2 - 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 (Ru II) 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.
AB - 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 (Ru II) 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.
UR - http://www.scopus.com/inward/record.url?scp=84875919097&partnerID=8YFLogxK
U2 - 10.1038/gt.2012.54
DO - 10.1038/gt.2012.54
M3 - Article
AN - SCOPUS:84875919097
SN - 0969-7128
VL - 20
SP - 435
EP - 443
JO - Gene Therapy
JF - Gene Therapy
IS - 4
ER -
