Drug evaluation based on phosphomimetic PDHA1 reveals the complexity of activity-related cell death in A549 non-small cell lung cancer cells
| Autor: | Sung-Jin Bae, Jung Ho Han, Sungmi Park, Jae Ho Kim, Bo-Sung Kim, Ki-Tae Ha, Ling Jin, Min-Kyoung Cho, Inkyu Lee, Dongryeol Ryu |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Programmed cell death
Lung Neoplasms Cell Apoptosis Endogeny PDK Biochemistry Article PDHA1 Carcinoma Non-Small-Cell Lung medicine Humans Pyruvate Dehydrogenase (Lipoamide) Glycolysis Enzyme Inhibitors Phosphorylation Molecular Biology A549 cell Chemistry General Medicine medicine.anatomical_structure A549 Cells Cytoplasm Cancer cell Cancer research Drug Evaluation Warburg effect |
| Zdroj: | BMB Reports |
| ISSN: | 1976-670X |
| DOI: | 10.5483/bmbrep.2021.54.11.101 |
| Popis: | Cancer cells predominantly generate energy via glycolysis, even in the presence of oxygen, to support abnormal cell proliferation. Suppression of PDHA1 by PDK1 prevents the conversion of cytoplasmic pyruvate into Acetyl-CoA. Several PDK inhibitors have been identified, but their clinical applications have not been successful for unclear reasons. In this study, endogenous PDHA1 in A549 cells was silenced by the CRISPR/Cas9 system, and PDHA1WT and PDHA13SD were transduced. Since PDHA13SD cannot be phosphorylated by PDKs, it was used to evaluate the specific activity of PDK inhibitors. This study highlights that PDHA1WT and PDHA13SD A549 cells can be used as a cell-based PDK inhibitor-distinction system to examine the relationship between PDH activity and cell death by established PDK inhibitors. Leelamine, huzhangoside A and otobaphenol induced PDH activity-dependent apoptosis, whereas AZD7545, VER-246608 and DCA effectively enhanced PDHA1 activity but little toxic to cancer cells. Furthermore, the activity of phosphomimetic PDHA1 revealed the complexity of its regulation, which requires further in-depth investigation. [BMB Reports 2021; 54(11): 563-568]. |
| Databáze: | OpenAIRE |
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