Target Identification of Marine Natural Product Odoamide:Odoamide Induces Apoptotic Cell Death by Targeting ATPase Na+/K+ Transporting Subunit Alpha 1 (ATP1A1).

Marine natural products show a large variety of unique chemical structures and potent biological activities. Elucidating the target molecule and the mechanism of action is an essential and challenging step in drug development starting with a natural product. Odoamide, a member of aurilide-family isolated from Okinawan marine cyanobacterium, has been known to exhibit highly potent cytotoxicity against various cancer cell lines. In this study, we investigated the target protein and the cytotoxic mechanism of odoamide. Compared to existing anticancer agents, odoamide showed a unique fingerprint in the JFCR39 cancer cell panel and a characteristic pattern in gene expression profiling. Affinity chromatography utilizing a biologically active odoamide probe identified ATPase Na⁺/K⁺ transporting subunit alpha 1 (ATP1A1) as a specific binding protein. Additionally, cells resistant to odoamide were found to have mutations at Gly98 and Gly99 of the ATP1A1 protein. The apparently attenuated cytotoxic and apoptotic activities of odoamide in odoamide-resistant cells suggests that the induction of these activities by odoamide is critically dependent on its interaction with ATP1A1. We conclude that odoamide induces apoptotic cell death by targeting ATP1A1, and we discuss the impact of affinity-based target identification for natural products and the potential of ATP1A1 inhibitors for drug discovery.