Inhibition of kinase IKK\u03b2 suppresses cellular abnormalities induced by the human papillomavirus oncoprotein HPV 18E6

Mojgan Padash Barmchi,Ross L Cagan,Bing Zhang,Miranda Thomas,Arushi Vats,Jayashree V Thatte,Lawrence Banks

doi:10.1038/s41598-020-80193-5

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

Highlights

The availability of effective vaccines against the most prevalent high-risk Human papillomavirus (HPV) is expected to eventually reduce HPV-dependent tumors
We have previously shown that co-expression of E6 and human UBE3A in the developing fly eye leads to a disorganized, rough eye phenotype
In this study we identify IKKβ as a mediator of the HPV 18 E6 and human UBE3A (hUBE3A)-induced cellular defects in both fly and human cancer models

Summary

Introduction

The availability of effective vaccines against the most prevalent high-risk HPVs is expected to eventually reduce HPV-dependent tumors. Interaction of the PBM with the PDZ domains of key host cellular PDZ domain proteins, including Magi, Dlg and Scribble, targets these proteins for ubiquitination and subsequent proteasome-mediated destruction[16,17,18,19]. These PDZ domain-containing proteins are important components of tight junctions and cell polarity-controlling c omplexes[20,21,22]. Reduction in IKKβ suppressed the cellular transformation caused by the cooperative action of HPVE6 and oncogenic Ras. we used a targeted inhibitor to demonstrate that reduced IKKβ activity results in strongly reduced growth of cultured human cervical cancer cells of established cell lines. Our results support the view that targeting IKKβ is a candidate strategy for developing novel lead therapeutics for HPV-induced cancer

Methods

Results

Conclusion