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

doi:10.3390/biomedicines9121907

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Title:	8-Hydroxydaidzein Downregulates JAK/STAT, MMP, Oxidative Phosphorylation, and PI3K/AKT Pathways in K562 Cells
Authors:	Wu, Pei-Shan Wang, Chih-Yang Chen, Pin-Shern Hung, Jui-Hsiang Yen, Jui-Hung Wu, Ming-Jiuan
Contributors:	Chia Nan Univ Pharm & Sci, Dept Appl Life Sci & Hlth Taipei Med Univ, Ph Program Canc Mol Biol & Drug Discovery Taipei Med Univ, Grad Inst Canc Biol & Drug Discovery Chia Nan Univ Pharm & Sci, Dept Biotechnol Tzu Chi Univ, Dept Mol Biol & Human Genet Tzu Chi Univ, Inst Med Sci
Keywords:	K562 8-hydroxydaidzein JAK STAT MMP OXPHOS AKT
Date:	2021
Issue Date:	2023-11-11 11:43:32 (UTC+8)
Publisher:	MDPI
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.
Relation:	BIOMEDICINES, v.9, n.12, pp.1907
Appears in Collections:	[Dept. of Life and Health Science] Periodical Articles [Dept. of Biotechnology (including master's program)] Periodical Articles

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