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Suppression of DYRK1A/B Drives Endoplasmic Reticulum Stress-mediated Autophagic Cell Death Through Metabolic Reprogramming in Colorectal Cancer Cells

Authors
 Jieon Hwang  ;  Areum Park  ;  Chinwoo Kim  ;  Danbi Yu  ;  Hyungju Byun  ;  Minhee Ku  ;  Jaemoon Yang  ;  Tae Il Kim  ;  Kyu-Sung Jeong  ;  Ki Young Kim  ;  Hyuk Lee  ;  Sang Joon Shin 
Citation
 ANTICANCER RESEARCH, Vol.42(1) : 589-598, 2022-01 
Journal Title
ANTICANCER RESEARCH
ISSN
 0250-7005 
Issue Date
2022-01
MeSH
Animals ; Apoptosis / drug effects ; Autophagic Cell Death / drug effects* ; Autophagy / drug effects ; Cell Line, Tumor ; Cell Proliferation / drug effects ; Cellular Reprogramming / genetics ; Colorectal Neoplasms / drug therapy* ; Colorectal Neoplasms / genetics ; Colorectal Neoplasms / pathology ; Endoplasmic Reticulum / drug effects ; Endoplasmic Reticulum / genetics ; Endoplasmic Reticulum Stress / drug effects* ; Enzyme Inhibitors / pharmacology* ; Fluorouracil / pharmacology ; Glycolysis / drug effects ; Humans ; Metabolic Networks and Pathways / drug effects ; Mice ; Protein Serine-Threonine Kinases / antagonists & inhibitors ; Protein Serine-Threonine Kinases / genetics* ; Protein-Tyrosine Kinases / antagonists & inhibitors ; Protein-Tyrosine Kinases / genetics* ; Reactive Oxygen Species / metabolism ; Xenograft Model Antitumor Assays
Keywords
DYRK1A protein ; DYRK1B protein ; autophagy ; colorectal cancer ; endoplasmic reticulum stress ; protein kinases
Abstract
Background/aim: We previously identified KS40008 (4-(3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzene-1,2-diol), a novel inhibitor of dual-specificity tyrosine phosphorylation-regulated kinase family (DYRK) 1A/B, which exhibited high enzymatic activity and cell proliferation-inhibitory effects in colorectal cancer (CRC) cell lines. In the present study, we aimed to elucidate the antitumor mechanisms of KS40008.

Materials and methods: To assess the cytotoxicity of KS40008, we utilized a human cell line and organoid model and performed a CCK-8 assay and real-time cell analysis. Mitochondrial function was determined through mitochondrial staining, mito-stress test, and glycolysis test. In addition, we investigated the mechanisms of cancer cell death induced by KS40008 through immunoblotting, real-time quantitative polymerase chain reaction, reactive oxygen species staining, and immunofluorescence staining.

Results: KS40008 exhibited significant cytotoxicity in CRC and non-CRC cell lines, and organoid models compared to 5-fluorouracil, a conventional chemotherapeutic drug. Moreover, KS40008-induced inhibition of DYRK1A/B led to mitochondrial dysfunction and endoplasmic reticulum stress, promoting autophagic cancer cell death.

Conclusion: KS40008 exerts antitumor activity through the inhibition of DYRK1A/B. Here, we demonstrated a mechanism by which KS40008 affects endoplasmic reticulum stress-mediated autophagy through the induction of mitochondrial stress, leading to cytotoxicity in CRC.
Full Text
https://ar.iiarjournals.org/content/42/1/589.long
DOI
10.21873/anticanres.15516
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
Yonsei Authors
Ku, Min Hee(구민희) ORCID logo https://orcid.org/0000-0002-1674-1474
Kim, Tae Il(김태일) ORCID logo https://orcid.org/0000-0003-4807-890X
Shin, Sang Joon(신상준) ORCID logo https://orcid.org/0000-0001-5350-7241
Yang, Jae Moon(양재문) ORCID logo https://orcid.org/0000-0001-7365-0395
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/187886
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