Photoaffinity Probe Reveals the Potential Target of Harringtonolide for Cancer Cell Migration Inhibition
Tian-Yu Zhu1, Xiu-Tao Wu1, Chen Chen1
1Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Harringtonolide (HO, 1) is a bioactive diterpenoid tropone isolated from Cephalotaxus harringtonia with antiproliferation activity. Until now there have been no reports to elucidate its anticancer mechanism. Herein we report the synthesis of HO-derived probes (10, 11, and 12) to identify the possible target of HO. As a result, the application of a novel photoaffinity alkyne-tagged probe from HO (compound 12) showed direct engagement between HO and receptor for activated C kinase 1 (RACK1). Furthermore, HO could suppress the epithelial-mesenchymal transition (EMT) process and inhibit activation of the FAK/Src/STAT3 signaling pathway in A375 cells. This study provides a groundwork for HO as an effective antitumor agent that targets RACK1 to suppress cancer cell migration.
Harringtonolide (HO, 1) is a bioactive diterpenoid tropone isolated from Cephalotaxus harringtonia with antiproliferation activity. Until now there have been no reports to elucidate its anticancer mechanism. Herein we report the synthesis of HO-derived probes (10, 11, and 12) to identify the possible target of HO. As a result, the application of a novel photoaffinity alkyne-tagged probe from HO (compound 12) showed direct engagement between HO and receptor for activated C kinase 1 (RACK1). Furthermore, HO could suppress the epithelial-mesenchymal transition (EMT) process and inhibit activation of the FAK/Src/STAT3 signaling pathway in A375 cells. This study provides a groundwork for HO as an effective antitumor agent that targets RACK1 to suppress cancer cell migration.
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