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8-羟基大豆苷元下调K562细胞中的JAK/STAT、MMP、氧化磷酸化和PI3K/AKT信号通路。

8-Hydroxydaidzein Downregulates JAK/STAT, MMP, Oxidative Phosphorylation, and PI3K/AKT Pathways in K562 Cells.

作者信息

Wu Pei-Shan, Wang Chih-Yang, Chen Pin-Shern, Hung Jui-Hsiang, Yen Jui-Hung, Wu Ming-Jiuan

机构信息

Department of Applied Life Science and Health, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan.

Ph.D. Program for Cancer Molecular Biology and Drug Discovery, Taipei Medical University, Taipei 11031, Taiwan.

出版信息

Biomedicines. 2021 Dec 14;9(12):1907. doi: 10.3390/biomedicines9121907.

DOI:10.3390/biomedicines9121907
PMID:34944720
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8698423/
Abstract

A metabolite isolated from fermented soybean, 8-hydroxydaidzein (8-OHD, 7,8,4'-trihydroxyisoflavone, NSC-678112), is widely used in ethnopharmacological research due to its anti-proliferative and anti-inflammatory effects. We reported previously that 8-OHD provoked reactive oxygen species (ROS) overproduction, and induced autophagy, apoptosis, breakpoint cluster region-Abelson murine leukemia viral oncogene (BCR-ABL) degradation, and differentiation in K562 human chronic myeloid leukemia (CML) cells. However, how 8-OHD regulates metabolism, the extracellular matrix during invasion and metastasis, and survival signaling pathways in CML remains largely unexplored. High-throughput technologies have been widely used to discover the therapeutic targets and pathways of drugs. Bioinformatics analysis of 8-OHD-downregulated differentially expressed genes (DEGs) revealed that Janus kinase/signal transducer and activator of transcription (JAK/STAT), matrix metalloproteinases (MMPs), c-Myc, phosphoinositide 3-kinase (PI3K)/AKT, and oxidative phosphorylation (OXPHOS) metabolic pathways were significantly altered by 8-OHD treatment. Western blot analyses validated that 8-OHD significantly downregulated cytosolic JAK2 and the expression and phosphorylation of STAT3 dose- and time-dependently in K562 cells. Zymography and transwell assays also confirmed that K562-secreted MMP9 and invasion activities were dose-dependently inhibited by 8-OHD after 24 h of treatment. RT-qPCR analyses verified that 8-OHD repressed metastasis and OXPHOS-related genes. In combination with DisGeNET, it was found that 8-OHD's downregulation of PI3K/AKT is crucial for controlling CML development. A STRING protein-protein interaction analysis further revealed that AKT and MYC are hub proteins for cancer progression. Western blotting revealed that AKT phosphorylation and nuclear MYC expression were significantly inhibited by 8-OHD. Collectively, this systematic investigation revealed that 8-OHD exerts anti-CML effects by downregulating JAK/STAT, PI3K/AKT, MMP, and OXPHOS pathways, and MYC expression. These results could shed new light on the development of 8-OHD for CML therapy.

摘要

一种从发酵大豆中分离出的代谢产物8-羟基大豆苷元（8-OHD，7,8,4'-三羟基异黄酮，NSC-678112），因其具有抗增殖和抗炎作用而被广泛应用于民族药理学研究。我们之前报道过，8-OHD可引发活性氧（ROS）过量产生，并诱导K562人慢性髓性白血病（CML）细胞发生自噬、凋亡、断裂点簇集区-阿贝尔森鼠白血病病毒癌基因（BCR-ABL）降解及分化。然而，8-OHD如何调节CML中的代谢、侵袭和转移过程中的细胞外基质以及生存信号通路，在很大程度上仍未得到探索。高通量技术已被广泛用于发现药物的治疗靶点和途径。对8-OHD下调的差异表达基因（DEG）进行生物信息学分析发现，8-OHD处理可显著改变Janus激酶/信号转导及转录激活因子（JAK/STAT）、基质金属蛋白酶（MMP）、c-Myc、磷脂酰肌醇3-激酶（PI3K）/AKT和氧化磷酸化（OXPHOS）代谢途径。蛋白质印迹分析证实，8-OHD可显著下调K562细胞中胞质JAK2以及STAT3的表达和磷酸化，且呈剂量和时间依赖性。酶谱分析和Transwell实验还证实，8-OHD处理24小时后，可剂量依赖性抑制K562细胞分泌的MMP9及侵袭活性。逆转录-定量聚合酶链反应（RT-qPCR）分析验证了8-OHD可抑制转移和OXPHOS相关基因。结合DisGeNET发现，8-OHD对PI3K/AKT的下调对于控制CML发展至关重要。STRING蛋白质-蛋白质相互作用分析进一步表明，AKT和MYC是癌症进展的枢纽蛋白。蛋白质印迹显示，8-OHD可显著抑制AKT磷酸化和核MYC表达。总体而言，这项系统研究表明，8-OHD通过下调JAK/STAT、PI3K/AKT、MMP和OXPHOS途径以及MYC表达发挥抗CML作用。这些结果可为8-OHD用于CML治疗的开发提供新的思路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9d1/8698423/d0fc2a22eeb4/biomedicines-09-01907-g009a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9d1/8698423/1b511e05e0dc/biomedicines-09-01907-g001a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9d1/8698423/ea8a8235b345/biomedicines-09-01907-g002a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9d1/8698423/de353981d01b/biomedicines-09-01907-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9d1/8698423/df96a7121b80/biomedicines-09-01907-g004a.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9d1/8698423/bce9a94e2072/biomedicines-09-01907-g006a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9d1/8698423/34482df78339/biomedicines-09-01907-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9d1/8698423/5f751869b99d/biomedicines-09-01907-g008a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9d1/8698423/d0fc2a22eeb4/biomedicines-09-01907-g009a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9d1/8698423/1b511e05e0dc/biomedicines-09-01907-g001a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9d1/8698423/ea8a8235b345/biomedicines-09-01907-g002a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9d1/8698423/de353981d01b/biomedicines-09-01907-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9d1/8698423/df96a7121b80/biomedicines-09-01907-g004a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9d1/8698423/d35c8a0cb481/biomedicines-09-01907-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9d1/8698423/bce9a94e2072/biomedicines-09-01907-g006a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9d1/8698423/34482df78339/biomedicines-09-01907-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9d1/8698423/5f751869b99d/biomedicines-09-01907-g008a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9d1/8698423/d0fc2a22eeb4/biomedicines-09-01907-g009a.jpg

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