Icaritin inhibits CDK2 expression and activity to interfere with tumor progression

Icaritin has shown antitumor activity in a variety of human solid tumors and myeloid leukemia cells. However, the direct target of icaritin and the underlying mechanisms remain unclear. In our study, CDK2 was found to be a direct target of icaritin in tumor cells. On one hand, icaritin interacted with CDK2 and interfered with CDK2/CyclinE complex formation, resulting in downregulation of CDK2 activity as illustrated with attenuated phosphorylation of FOXO1, Rb, and P27, and E2F/Rb dissociation. On the other hand, icaritin reduced the stability and translation efficiency of CDK2-mRNA by modulating microRNA-597 expression. To be of functional importance, icaritin inhibited proliferation and promoted apoptosis of tumor cells in vitro and in vivo, which was consistent with CDK2 inhibitors—k03861. Our data revealed CDK2 as the direct target of icaritin for its antitumor effects, which may suggest new therapeutics of icaritin or combinational therapeutics involving both icaritin and CDK2 inhibitors for cancers.