TY - JOUR

T1 - Inhibition of kinase IKKβ suppresses cellular abnormalities induced by the human papillomavirus oncoprotein HPV 18E6

AU - Padash Barmchi, Mojgan

AU - Thomas, Miranda

AU - Thatte, Jayashree V.

AU - Vats, Arushi

AU - Zhang, Bing

AU - Cagan, Ross L.

AU - Banks, Lawrence

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85099420860&partnerID=8YFLogxK

U2 - 10.1038/s41598-020-80193-5

DO - 10.1038/s41598-020-80193-5

M3 - Journal article

C2 - 33441820

AN - SCOPUS:85099420860

VL - 11

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 1111

ER -