8-hydroxydaidzein downregulates JAK/STAT, MMP, oxidative phosphorylation, and PI3K/AKT pathways in K562 cells

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

Research output: Contribution to journalArticlepeer-review

Abstract

A metabolite isolated from fermented soybean, 8-hydroxydaidzein (8-OHD, 7,8,4′-trihy-droxyisoflavone, NSC-678112), is widely used in ethnopharmacological research due to its anti-pro-liferative 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 downregu-lated 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.

Original languageEnglish
Article number1907
JournalBiomedicines
Volume9
Issue number12
DOIs
Publication statusPublished - Dec 2021

Keywords

  • 8-hydroxydaidzein
  • AKT
  • JAK/STAT
  • K562
  • MMP
  • OXPHOS

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint

Dive into the research topics of '8-hydroxydaidzein downregulates JAK/STAT, MMP, oxidative phosphorylation, and PI3K/AKT pathways in K562 cells'. Together they form a unique fingerprint.

Cite this