5-Hydroxymethyl-Furfural and Structurally Related Compounds Block the Ion Conductance in Human Aquaporin-1 Channels and Slow Cancer Cell Migration and Invasion
5-Hydroxymethyl-Furfural and Structurally Related Compounds Block the Ion Conductance in Human Aquaporin-1 Channels and Slow Cancer Cell Migration and Invasion
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DOI：
10.1124/mol.119.119172
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发表时间：
2020-07-01
影响因子：
3.6
通讯作者：
Yool, Andrea J.
中科院分区：
文献类型：
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作者：
Chow, Pak Hin;Kourghi, Mohamad;Yool, Andrea J.
水通道蛋白-1 （Aquaporin-1, AQP1）双水离子通道在某些类型癌细胞的前缘上调时，可增强迁移和侵袭。这里的工作确定了结构相关的呋喃化合物作为AQP1离子通道的新型抑制剂。分析了天然药用蜂蜜成分5-羟甲基-2-糠醛（5HMF）和3个结构相关化合物5-n -硝基-2-呋喃酸（5NFA）、5-乙酰乙炔乙基-2-呋喃醛（5AMF）、甲基-5-硝基-2-呋喃酸（M5NF）对爪蟾卵母细胞中表达的人类AQP1通道水通道和离子通道活性的影响。双电极电压钳显示5HMF （IC50为0.43 mM）、5NFA （IC50为1.2 mM）和5AMF （IC50与3 mM相似）对AQP1离子电流的阻断呈剂量依赖性，但M5NF没有抑制作用。在硅对接预测活性配体与甘氨酸165相互作用，位于环D门控域周围的四聚体中心孔的细胞内前庭。通过亚单位内不同孔隙的水通量不受呋喃化合物的影响（浓度高达5毫米）。在高表达aqp1的癌细胞系、结肠癌（HT29）、表达aqp1的乳腺癌（MDA）和低表达aqp1的SW480中检测了其对细胞迁移、侵袭和体外细胞骨架组织的影响。5HMF、5NFA和5AMF选择性地损害AQP1富集细胞系的细胞运动。相反，M5NF通过破坏肌动蛋白细胞骨架来固定所有癌细胞系。在有效阻断运动的剂量下未观察到细胞活力的降低。这些结果将呋喃定义为一类新的AQP1离子通道抑制剂，可用于基础研究和潜在的先导化合物，用于开发靶向水通道蛋白活性的治疗剂。结论：5-羟甲基-2-糠醛（5HMF）是天然药用蜂蜜的一种成分，它可以阻断离子电导，但不能阻断人类水通道蛋白1 （AQP1）通道的水通量，并损害AQP1依赖性细胞在癌细胞系中的迁移和侵袭性。在硅对接模型的支持下，5HMT和结构类似物的分析证明了呋喃化合物的结构-活性关系。这项工作为国际上的研究人员确定了新的低成本AQP1药物拮抗剂。呋喃类化合物作为一类控制肿瘤转移的新型治疗剂值得考虑。
Aquaporin-1 (AQP1) dual water and ion channels enhance migration and invasion when upregulated in leading edges of certain classes of cancer cells. Work here identifies structurally related furan compounds as novel inhibitors of AQP1 ion channels. 5-Hydroxymethyl-2-furfural (5HMF), a component of natural medicinal honeys, and three structurally related compounds, 5-n itro-2-furoic acid (5NFA), 5-acetoxynnethyl-2-furaldehyde (5AMF), and methyl-5-nitro-2-furoate (M5NF), were analyzed for effects on water and ion channel activities of human AQP1 channels expressed in Xenopus oocytes. Two-electrode voltage clamp showed dose-dependent block of the AQP1 ion current by 5HMF (IC50 0.43 mM), 5NFA (IC50 1.2 mM), and 5AMF (IC50 similar to 3 mM) but no inhibition by M5NF. In silico docking predicted the active ligands interacted with glycine 165, located in loop D gating domains surrounding the intracellular vestibule of the tetrameric central pore. Water fluxes through separate intrasubunit pores were unaltered by the furan compounds (at concentrations up to 5 mM). Effects on cell migration, invasion, and cytoskeletal organization in vitro were tested in high-AQP1-expressing cancer lines, colon cancer (HT29) and AQP1-expressing breast cancer (MDA), and low-AQP1-expressing SW480. 5HMF, 5NFA, and 5AMF selectively impaired cell motility in the AQP1 -enriched cell lines. In contrast, M5NF immobilized all the cancer lines by disrupting actin cytoskeleton. No reduction in cell viability was observed at doses that were effective in blocking motility. These results define furans as a new class of AQP1 ion channel inhibitors for basic research and potential lead compounds for development of therapeutic agents targeting aquaporin channel activity.SIGNIFICANCE STATEMENT5-Hydroxymethyl-2-furfural (5HMF), a component of natural medicinal honeys, blocks the ion conductance but not the water flux through human Aquaporin-1 (AQP1) channels and impairs AQP1 -dependent cell migration and invasiveness in cancer cell lines. Analyses of 5HMT and structural analogs demonstrate a structure-activity relationship for furan compounds, supported by in silico docking modeling. This work identifies new low-cost pharmacological antagonists for AQP1 available to researchers internationally. Furans merit consideration as a new class of therapeutic agents for controlling cancer metastasis.