Suppression of DYRK1A/B Drives Endoplasmic Reticulum Stress-mediated Autophagic Cell Death Through Metabolic Reprogramming in Colorectal Cancer Cells
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| Názov: | Suppression of DYRK1A/B Drives Endoplasmic Reticulum Stress-mediated Autophagic Cell Death Through Metabolic Reprogramming in Colorectal Cancer Cells |
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| Autori: | 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 |
| Prispievatelia: | 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, Ku, Min Hee |
| Zdroj: | Anticancer Research. 42:589-598 |
| Informácie o vydavateľovi: | International Institute of Anticancer Research, 2021. |
| Rok vydania: | 2021 |
| Predmety: | 0301 basic medicine, Apoptosis, Endoplasmic Reticulum, Colorectal Neoplasms / genetics, Mice, Protein Serine-Threonine Kinases / antagonists & inhibitors, Autophagic Cell Death / drug effects, Enzyme Inhibitors, 0303 health sciences, Tumor, Fluorouracil / pharmacology, Protein Serine-Threonine Kinases / genetics, Protein-Tyrosine Kinases / antagonists & inhibitors, Protein-Tyrosine Kinases, Cellular Reprogramming, Endoplasmic Reticulum Stress, Colorectal Neoplasms / drug therapy, 3. Good health, DYRK1A protein, endoplasmic reticulum stress, Fluorouracil, Colorectal Neoplasms, Glycolysis, Metabolic Networks and Pathways, autophagy, Autophagic Cell Death, colorectal cancer, Protein Serine-Threonine Kinases, Apoptosis / drug effects, Cellular Reprogramming / genetics, Colorectal Neoplasms / pathology, Cell Line, 03 medical and health sciences, Cell Line, Tumor, Autophagy / drug effects, Autophagy, Endoplasmic Reticulum / drug effects, Animals, Humans, Metabolic Networks and Pathways / drug effects, Glycolysis / drug effects, Cell Proliferation, Enzyme Inhibitors / pharmacology, protein kinases, Endoplasmic Reticulum Stress / drug effects, Protein-Tyrosine Kinases / genetics, Reactive Oxygen Species / metabolism, Endoplasmic Reticulum / genetics, Xenograft Model Antitumor Assays, DYRK1B protein, Cell Proliferation / drug effects, Reactive Oxygen Species |
| Popis: | 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.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.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.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. |
| Druh dokumentu: | Article |
| Jazyk: | English |
| ISSN: | 1791-7530 0250-7005 |
| DOI: | 10.21873/anticanres.15516 |
| Prístupová URL adresa: | https://pubmed.ncbi.nlm.nih.gov/34969768 |
| Rights: | CC BY NC ND |
| Prístupové číslo: | edsair.doi.dedup.....b8651a48bd784b5b6fecb999294e5981 |
| Databáza: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | 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.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.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.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. |
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| ISSN: | 17917530 02507005 |
| DOI: | 10.21873/anticanres.15516 |