The oncogenic role of ATP-sensitive potassium ion (KATP) channels in human papillomavirus (HPV)-positive cancer cells

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. This study demonstrates 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 (KATP) channels, we reveal that these channels are active in HPV-positive cells and that this activity is necessary for HPV oncoprotein expression. Further, expression of SUR1, which forms the regulatory subunit of the multimeric channel complex, was found to be upregulated in a manner dependent on the E7 oncoprotein and likely involving the host transcription factor SP1. Importantly, knockdown of KATP channel subunits significantly impeded cell proliferation via induction of a G1 phase cell cycle arrest. This was confirmed both in vitro and in in vivo tumourigenicity assays. However, KATP channel activity was not found to be critical for the survival of HPV+ cancer cells. Mechanistically, it is proposed that the pro-proliferative effect of KATP channels is mediated via the activation of a MAPK/AP-1 signalling axis. Finally, the significance of KATP channels in HPV+ oropharyngeal cancers was assessed. Surprisingly, it was discovered that, in contrast to cervical cancer, depletion of KATP channel subunits had little impact on HPV gene expression or cell proliferation. Further research to undertake a complete characterisation of the role of KATP channels in all HPV-associated diseases is now warranted in order to determine whether the clinically available inhibitors of these channels could represent an effective therapeutic option.