Xanthohumol inhibits non‐small cell lung cancer via directly targeting T‐lymphokine‐activated killer cell‐originated protein kinase

Abstract

Xanthohumol is a principal prenylated chalcone isolated from hops. Previous studies have shown that xanthohumol was effective against various types of cancer, but the mechanisms, especially the direct targets for xanthohumol to exert an anticancer effect, remain elusive. Overexpression of T-lymphokine-activated killer celloriginated protein kinase (TOPK) promotes tumorigenesis, invasion and metastasis, implying the likely potential for targeting TOPK in cancer prevention and treatment.In the present study, we found that xanthohumol significantly inhibited the cell proliferation, migration and invasion of non-small cell lung cancer (NSCLC) in vitro and suppressed tumor growth in vivo, which is well correlated with inactivating TOPK, evidenced by reduced phosphorylation of TOPK and its downstream signaling histone H3 and Akt, and decreased its kinase activity. Moreover, molecular docking and biomolecular interaction analysis showed that xanthohumol was able to directly bind to the TOPK protein, suggesting that TOPK inactivation by xanthohumol is attributed to its ability to directly interact with TOPK. The findings of the present study identified TOPK as a direct target for xanthohumol to exert its anticancer activity, revealing novel insight into the mechanisms underlying the anticancer activity of xanthohumol.

Anticancer Potential of Natural Chalcones: In Vitro and In Vivo Evidence

“…Immunohistochemical staining showed in vivo reduced expression of Ki-67, cyclin D1, and Fra1 with concurrent upregulation of the proapoptotic protein PUMA. All of the aforementioned results demonstrate the potential of XH as an anti-tumor agent for the management of lung cancer [ 170 , 171 , 177 ].…”

“…Treatment with XH significantly reduced the phosphorylation of TOPK as well as its downstream signaling molecules Akt and histone H3 in A549 and HCC827 cells and also suppressed its kinase activity. Biomolecular interaction analysis showed that this effect is mediated by direct interaction between XH and TOPK [ 177 ]. The targets of XH also include topoisomerases, enzymes essential for DNA relaxation during replication, transcription, mitosis, and other processes.…”