Description:
<jats:p>Xanthohumol (<jats:styled-content style="fixed-case">XN</jats:styled-content>), a simple prenylated chalcone, can be isolated from hops and has the potential to be a cancer chemopreventive agent against several human tumor cell lines. We previously identified valosin‐containing protein (<jats:styled-content style="fixed-case">VCP</jats:styled-content>) as a target of <jats:styled-content style="fixed-case">XN</jats:styled-content>;<jats:styled-content style="fixed-case"> VCP</jats:styled-content> can also play crucial roles in cancer progression and prognosis. Therefore, we investigated the molecular mechanisms governing the contribution of <jats:styled-content style="fixed-case">VCP</jats:styled-content> to the antitumor activity of <jats:styled-content style="fixed-case">XN</jats:styled-content>. Several human tumor cell lines were treated with <jats:styled-content style="fixed-case">XN</jats:styled-content> to investigate which human tumor cell lines are sensitive to <jats:styled-content style="fixed-case">XN</jats:styled-content>. Several cell lines exhibited high sensitivity to <jats:styled-content style="fixed-case">XN</jats:styled-content> both <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic>. sh<jats:styled-content style="fixed-case">RNA</jats:styled-content> screening and bioinformatics analysis identified that the inhibition of the adenylate cyclase (<jats:styled-content style="fixed-case">AC</jats:styled-content>) pathway synergistically facilitated apoptosis induced by <jats:styled-content style="fixed-case">VCP</jats:styled-content> inhibition. These results suggest that there is crosstalk between the <jats:styled-content style="fixed-case">AC</jats:styled-content> pathway and <jats:styled-content style="fixed-case">VCP</jats:styled-content> function, and targeting both <jats:styled-content style="fixed-case">VCP</jats:styled-content> and the <jats:styled-content style="fixed-case">AC</jats:styled-content> pathway is a potential chemotherapeutic strategy for a subset of tumor cells.</jats:p>