Inhibition of kinase IKKβ suppresses cellular abnormalities induced by the human papillomavirus oncoprotein HPV 18E6

Abstract Human papillomavirus (HPV) is the leading cause of cervical cancer and has been implicated in several other cancer types including vaginal, vulvar, penile, and oropharyngeal cancers. Despite the recent availability of a vaccine, there are still over 310,000 deaths each year worldwide. Curre...

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Autores principales:	Mojgan Padash Barmchi, Miranda Thomas, Jayashree V. Thatte, Arushi Vats, Bing Zhang, Ross L. Cagan, Lawrence Banks
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7444da68b90b44009b1780a02e5e7108
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spelling	oai:doaj.org-article:7444da68b90b44009b1780a02e5e71082021-12-02T14:12:07ZInhibition of kinase IKKβ suppresses cellular abnormalities induced by the human papillomavirus oncoprotein HPV 18E610.1038/s41598-020-80193-52045-2322https://doaj.org/article/7444da68b90b44009b1780a02e5e71082021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80193-5https://doaj.org/toc/2045-2322Abstract Human papillomavirus (HPV) is the leading cause of cervical cancer and has been implicated in several other cancer types including vaginal, vulvar, penile, and oropharyngeal cancers. Despite the recent availability of a vaccine, there are still over 310,000 deaths each year worldwide. Current treatments for HPV-mediated cancers show limited efficacy, and would benefit from improved understanding of disease mechanisms. Recently, we developed a Drosophila ‘HPV 18 E6’ model that displayed loss of cellular morphology and polarity, junctional disorganization, and degradation of the major E6 target Magi; we further provided evidence that mechanisms underlying HPV E6-induced cellular abnormalities are conserved between humans and flies. Here, we report a functional genetic screen of the Drosophila kinome that identified IKK $$\beta$$ β —a regulator of NF-κB—as an enhancer of E6-induced cellular defects. We demonstrate that inhibition of IKK $$\beta$$ β reduces Magi degradation and that this effect correlates with hyperphosphorylation of E6. Further, the reduction in IKK $$\beta$$ β suppressed the cellular transformation caused by the cooperative action of HPVE6 and the oncogenic Ras. Finally, we demonstrate that the interaction between IKK $$\beta$$ β and E6 is conserved in human cells: inhibition of IKK $$\beta$$ β blocked the growth of cervical cancer cells, suggesting that IKK $$\beta$$ β may serve as a novel therapeutic target for HPV-mediated cancers.Mojgan Padash BarmchiMiranda ThomasJayashree V. ThatteArushi VatsBing ZhangRoss L. CaganLawrence BanksNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mojgan Padash Barmchi Miranda Thomas Jayashree V. Thatte Arushi Vats Bing Zhang Ross L. Cagan Lawrence Banks Inhibition of kinase IKKβ suppresses cellular abnormalities induced by the human papillomavirus oncoprotein HPV 18E6
description	Abstract Human papillomavirus (HPV) is the leading cause of cervical cancer and has been implicated in several other cancer types including vaginal, vulvar, penile, and oropharyngeal cancers. Despite the recent availability of a vaccine, there are still over 310,000 deaths each year worldwide. Current treatments for HPV-mediated cancers show limited efficacy, and would benefit from improved understanding of disease mechanisms. Recently, we developed a Drosophila ‘HPV 18 E6’ model that displayed loss of cellular morphology and polarity, junctional disorganization, and degradation of the major E6 target Magi; we further provided evidence that mechanisms underlying HPV E6-induced cellular abnormalities are conserved between humans and flies. Here, we report a functional genetic screen of the Drosophila kinome that identified IKK $$\beta$$ β —a regulator of NF-κB—as an enhancer of E6-induced cellular defects. We demonstrate that inhibition of IKK $$\beta$$ β reduces Magi degradation and that this effect correlates with hyperphosphorylation of E6. Further, the reduction in IKK $$\beta$$ β suppressed the cellular transformation caused by the cooperative action of HPVE6 and the oncogenic Ras. Finally, we demonstrate that the interaction between IKK $$\beta$$ β and E6 is conserved in human cells: inhibition of IKK $$\beta$$ β blocked the growth of cervical cancer cells, suggesting that IKK $$\beta$$ β may serve as a novel therapeutic target for HPV-mediated cancers.
format	article
author	Mojgan Padash Barmchi Miranda Thomas Jayashree V. Thatte Arushi Vats Bing Zhang Ross L. Cagan Lawrence Banks
author_facet	Mojgan Padash Barmchi Miranda Thomas Jayashree V. Thatte Arushi Vats Bing Zhang Ross L. Cagan Lawrence Banks
author_sort	Mojgan Padash Barmchi
title	Inhibition of kinase IKKβ suppresses cellular abnormalities induced by the human papillomavirus oncoprotein HPV 18E6
title_short	Inhibition of kinase IKKβ suppresses cellular abnormalities induced by the human papillomavirus oncoprotein HPV 18E6
title_full	Inhibition of kinase IKKβ suppresses cellular abnormalities induced by the human papillomavirus oncoprotein HPV 18E6
title_fullStr	Inhibition of kinase IKKβ suppresses cellular abnormalities induced by the human papillomavirus oncoprotein HPV 18E6
title_full_unstemmed	Inhibition of kinase IKKβ suppresses cellular abnormalities induced by the human papillomavirus oncoprotein HPV 18E6
title_sort	inhibition of kinase ikkβ suppresses cellular abnormalities induced by the human papillomavirus oncoprotein hpv 18e6
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/7444da68b90b44009b1780a02e5e7108
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Inhibition of kinase IKKβ suppresses cellular abnormalities induced by the human papillomavirus oncoprotein HPV 18E6

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