5α-Epoxyalantolactone Inhibits Metastasis of Triple-Negative Breast Cancer Cells by Covalently Binding a Conserved Cysteine of Annexin A2

Abstract

Triple-negative breast cancer (TNBC) has been considered the most aggressive and mortal breast cancer. Thus far, it remains an important challenge to develop TNBC targeted therapy. As revealed from numerous recent studies, ANXA2 may be a potential target to treat TNBC. In the present study, a natural product 5α-epoxyalantolactone (5α-EAL) was discovered as an anti-breast cancer stem cells (BCSCs) lead compound. Furthermore, 5α-EAL was found to be able to notably suppress the function of ANXA2 by covalently targeting cysteine 9 (Cys9) of ANXA2. To the best of our knowledge, 5α-EAL was recognized as the first small molecule functional inhibitor of ANXA2. It could significantly inhibit the formation of the heterotetrameric complex of ANXA2 and S100A10, which is capable of transporting E-cadherin (E-Ca) to the membrane. The above findings may be used as a possible strategy to develop novel anti-TNBC therapies targeting ANXA2.

Annexin A2 combined with TTK accelerates esophageal cancer progression via the Akt/mTOR signaling pathway

“…Therefore, therapeutic methods aimed at inhibiting EMT have great potential for preventing cancer metastasis and treating drug resistance. Currently, a small molecular function inhibitor of ANXA2, 5α-epoxyalantolactone (5α-EAL) is expected to become an effective treatment for breast cancer [ 60 ]. Therefore, we suspect that ANXA2 has the potential to be an EMT inhibitor and a new therapeutic target in ESCC.…”