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

Padash Barmchi, M., Thomas, M., Thatte, J. V., Vats, A., Zhang, B., Cagan, R. L. and Banks, L. (2021) Inhibition of kinase IKK β suppresses cellular abnormalities induced by the human papillomavirus oncoprotein HPV 18E6. Scientific Reports, 11, 1111. (doi: 10.1038/s41598-020-80193-5) (PMID:33441820) (PMCID:PMC7807017)

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 IKKβ—a regulator of NF-κB—as an enhancer of E6-induced cellular defects. We demonstrate that inhibition of IKKβ reduces Magi degradation and that this effect correlates with hyperphosphorylation of E6. Further, the reduction in IKKβ suppressed the cellular transformation caused by the cooperative action of HPVE6 and the oncogenic Ras. Finally, we demonstrate that the interaction between IKKβ and E6 is conserved in human cells: inhibition of IKKβ blocked the growth of cervical cancer cells, suggesting that IKKβ may serve as a novel therapeutic target for HPV-mediated cancers.

• Item Type: Articles
• Additional Information: This study was partially supported by Oklahoma Shared Clinical and Translational Resources grant funded by NIH.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cagan, Professor Ross
• Authors: Padash Barmchi, M., Thomas, M., Thatte, J. V., Vats, A., Zhang, B., Cagan, R. L., and Banks, L.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Scientific Reports
• Publisher: Nature Research
• ISSN: 2045-2322
• ISSN (Online): 2045-2322
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Scientific Reports 11: 1111
• Publisher Policy: Reproduced under a Creative Commons License