Abstract
Uncontrolled proliferation, a major feature of cancer cells, is often triggered by the malfunction of cell cycle regulators such as protein kinases. Recently, cell cycle-related protein kinases have become attractive targets for anti-cancer therapy, because they play fundamental roles in cellular proliferation. However, the protein kinase-targeted drugs that have been developed so far do not show impressive clinical results and also display severe side effects; therefore, there is undoubtedly a need to investigate new drugs targeting other protein kinases that are critical in cell cycle progression. Vaccinia-related kinase 1 (VRK1) is a mitotic kinase that functions in cell cycle regulation by phosphorylating cell cycle-related substrates such as barrier-to-autointegration factor (BAF), histone H3, and the cAMP response element (CRE)-binding protein (CREB). In our study, we identified luteolin as the inhibitor of VRK1 by screening a small-molecule natural compound library. Here, we evaluated the efficacy of luteolin as a VRK1-targeted inhibitor for developing an effective anti-cancer strategy. We confirmed that luteolin significantly reduces VRK1-mediated phosphorylation of the cell cycle-related substrates BAF and histone H3, and directly interacts with the catalytic domain of VRK1. In addition, luteolin regulates cell cycle progression by modulating VRK1 activity, leading to the suppression of cancer cell proliferation and the induction of apoptosis. Therefore, our study suggests that luteolin-induced VRK1 inhibition may contribute to establish a novel cell cycle-targeted strategy for anti-cancer therapy.
Highlights
Tumorigenesis is associated with a dysregulation of cell division, which is often triggered by defects in the regulation of protein modulators that play critical roles in cell cycle checkpoints and progression [1]
Luteolin is a potent inhibitor of Vaccinia-related kinase 1 (VRK1) kinase activity To examine whether luteolin could effectively suppress the enzymatic activity of VRK1, we performed an in vitro kinase assay and compared the inhibitory effects of luteolin with those of other flavonoid-like compounds
These results indicate that luteolin is a potent inhibitor of VRK1 kinase activity, which is required for the modulation of cell cycle progression
Summary
Tumorigenesis is associated with a dysregulation of cell division, which is often triggered by defects in the regulation of protein modulators that play critical roles in cell cycle checkpoints and progression [1]. Among the proteins that make up the cell cycle machinery, recent therapeutic strategies have attempted to take advantage of targeting several cell cycle protein kinases to enhance drug selectivity and therapeutic effectiveness [2,3]. Such cell cycle-related protein kinases have become attractive targets for anti-cancer therapy, owing to their fundamental functions in controlling cell growth. Effective inhibition of certain phase of cell cycle is still regarded as a valuable strategy to treat cancer, identification of novel, cell cycle-specific, druggable target proteins and the development of their selective inhibitors that might have potential to become chemotherapeutic agents are undoubtedly required
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
