Abstract
Many mitotic kinases have been targeted for the development of anti-cancer drugs, and inhibitors of these kinases have been expected to perform well for cancer therapy. Efforts focused on selecting good targets and finding specific drugs to target are especially needed, largely due to the increased frequency of anti-cancer drugs used in the treatment of lung cancer. Vaccinia-related kinase 1 (VRK1) is a master regulator in lung adenocarcinoma and is considered a key molecule in the adaptive pathway, which mainly controls cell survival. We found that ursolic acid (UA) inhibits the catalytic activity of VRK1 via direct binding to the catalytic domain of VRK1. UA weakens surveillance mechanisms by blocking 53BP1 foci formation induced by VRK1 in lung cancer cells, and possesses synergistic anti-cancer effects with DNA damaging drugs. Taken together, UA can be a good anti-cancer agent for targeted therapy or combination therapy with DNA damaging drugs for lung cancer patients.
Highlights
Block, the critical pathway for a specific cancer, the cancer cells could be targeted and killed
vaccinia-related kinase 1 (VRK1) acts as a mitotic kinase to promote cell cycle progression by phosphorylating various substrates, such as histone H3, CRE binding protein (CREB), and barrier-to-autointegration factor (BAF) during each phase of the cell cycle[6,7,10]
We showed that UA can inhibit the VRK1-mediated phosphorylation of both CREB and histone H3 in vivo, in a concentration-dependent manner (Fig. 1d,e)
Summary
Block, the critical pathway for a specific cancer, the cancer cells could be targeted and killed. VRK1 contributes to the G1 to S phase transition by phosphorylating CRE binding protein (CREB)[10] It phosphorylates several key transcription factors involved in cell division, including c-Jun[11] and activating transcription factor 2 (ATF2)[12] and has further been associated with G0 exit and G1 entry[13]. During the ionizing radiation (IR)-induced DNA damage response (DDR), VRK1 plays a role in formation of 53BP1 foci[15], a damage controlling complex. These critical roles for VRK1 suggest that it could be an excellent candidate for lung cancer therapy. We showed that simultaneous treatment of cancer cells with UA and DNA damaging drugs generates synergistic effects and confirms these findings in a mouse xenograft model
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