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Drug evaluation based on phosphomimetic PDHA1 reveals the complexity of activity–related cell death in A549 non-small cell lung cancer cells
Ling Jin 1,2 (Ph.D candidate), Minkyoung Cho 2 (Posdoc fellow), Bo-Sung Kim 1,2 (Ph.D candidate), Jung Ho Han 1,2 (Ph.D candidate), Sungmi Park 3 (Researcher), In-Kyu Lee 3,4 (Professor), Dongryeol Ryu 5 (Assistant Professor), Jae Ho Kim 6 (Professor), Sung-Jin Bae 2,# (Research Professor), Ki-Tae Ha 1,2,*,# (Professor)
1Department of Korean Medical Science, School of Korean Medicine and 2Korean Medical Research Center for Healthy Aging, Pusan National University,
3Department of Internal Medicine, School of Medicine and 4Research Institute of Aging and Metabolism, Kyungpook National University,
5Department of Molecular Cell Biology, School of Medicine, Sungkyunkwan University,
6Department of Physiology, College of Medicine, Pusan National University
Abstract
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.
Abstract, Accepted Manuscript(in press) [Submitted on July 26, 2021, Accepted on August 30, 2021]
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