Exploitation of ATP-sensitive potassium ion (K ATP ) channels by HPV promotes cervical cancer cell proliferation by contributing to MAPK/AP-1 signalling.

Autor: Scarth JA; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK.; Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK., Wasson CW; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK.; Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, LS2 9JT, UK., Patterson MR; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK., Evans D; Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, LS9 7TF, UK., Barba-Moreno D; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK., Carden H; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK., Cassidy R; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK., Whitehouse A; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK., Mankouri J; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK., Samson A; Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, LS9 7TF, UK., Morgan EL; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK. em715@sussex.ac.uk.; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK. em715@sussex.ac.uk.; School of Life Sciences, University of Sussex, Brighton, BN1 9QG, UK. em715@sussex.ac.uk., Macdonald A; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK. a.macdonald@leeds.ac.uk.; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK. a.macdonald@leeds.ac.uk.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2023 Aug; Vol. 42 (34), pp. 2558-2577. Date of Electronic Publication: 2023 Jul 13.
DOI: 10.1038/s41388-023-02772-w
Abstrakt: Persistent infection with high-risk human papillomaviruses (HPVs) is the causal factor in multiple human malignancies, including >99% of cervical cancers and a growing proportion of oropharyngeal cancers. Prolonged expression of the viral oncoproteins E6 and E7 is necessary for transformation to occur. Although some of the mechanisms by which these oncoproteins contribute to carcinogenesis are well-characterised, a comprehensive understanding of the signalling pathways manipulated by HPV is lacking. Here, we present the first evidence to our knowledge that the targeting of a host ion channel by HPV can contribute to cervical carcinogenesis. Through the use of pharmacological activators and inhibitors of ATP-sensitive potassium ion (K ATP ) channels, we demonstrate that these channels are active in HPV-positive cells and that this activity is required for HPV oncoprotein expression. Further, expression of SUR1, which forms the regulatory subunit of the multimeric channel complex, was found to be upregulated in both HPV+ cervical cancer cells and in samples from patients with cervical disease, in a manner dependent on the E7 oncoprotein. Importantly, knockdown of SUR1 expression or K ATP channel inhibition significantly impeded cell proliferation via induction of a G1 cell cycle phase arrest. This was confirmed both in vitro and in in vivo tumourigenicity assays. Mechanistically, we propose that the pro-proliferative effect of K ATP channels is mediated via the activation of a MAPK/AP-1 signalling axis. A complete characterisation of the role of K ATP channels in HPV-associated cancer is now warranted in order to determine whether the licensed and clinically available inhibitors of these channels could constitute a potential novel therapy in the treatment of HPV-driven cervical cancer.
(© 2023. The Author(s).)
Databáze: MEDLINE
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