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.