Potent Anticancer Activities of Beauvericin Against KB Cells <i>In Vitro</i> by Inhibiting the Expression of ACAT1 and Exploring Binding Affinity

Author(s):

Haiming Zhou, Jing Zhang, Xiaoqing Chen, Shili Guo, Huimei Lin, Bo Ding, Hongbo Huang* and Yiwen Tao*   Pages 897 - 904 ( 8 )

Abstract:

Background and Objective: Beauvericin (BEA), a cyclic hexadepsipeptide mycotoxin, is a potent inhibitor of the acyl-CoA: cholesterol acyltransferase enzyme 1 (ACAT1), involved in multiple tumor-correlated pathways. However, the binding mechanisms between BEA and ACAT1 were not elucidated. <P> Methods: BEA was purified from a mangrove entophytic <i>Fusarium</i> sp. KL11. Single-crystal X-ray diffraction was used to determine the structure of BEA. Wound healing assays of BEA against KB cell line and MDA-MB-231 cell line were evaluated. Inhibitory potency of BEA against ACAT1 was determined by ELISA assays. Molecular docking was carried out to illuminate the bonding mechanism between BEA and ACAT1. <P> Results: The structure of BEA was confirmed by X-ray diffraction, indicating a monoclinic crystal system with P21 space group (α = 90°, β = 92.2216(9)°, γ= 90°). BEA displayed migration-inhibitory activities against KB cells and MDA-MB-231 cells <i>In Vitro</i>. ELISA assays revealed that the protein expression level of ACAT1 in KB cells was significantly decreased after BEA treatment (P ＜0.05). Molecular docking demonstrated that BEA formed hydrogen bond with His425 and pi-pi staking with Tyr429 in ACAT1. <P> Conclusion: BEA sufficiently inhibited the proliferation and migration of KB cells and MDA-MB-231 cells by downregulating ACAT1 expression. In addition, BEA potentially possessed a strong binding affinity with ACAT1. BEA may serve as a potential lead compound for the development of a new ACAT1-targeted anticancer drug.

Keywords:

Beauvericin, crystal structure, migration, ELISA, molecular docking, ACAT1.

Affiliation:

Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436

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