title: A novel pyruvate kinase M2 activator compound that suppresses lung cancer cell viability under hypoxia.
abstract: Pyruvate kinase M2 isoform (PKM2), a rate-limiting enzyme in the final step of glycolysis, is known to be associated with the metabolic rewiring of cancer cells, and considered an important cancer therapeutic target. Herein, we report a novel PKM2 activator, PA-12, which was identified via the molecular docking-based virtual screening. We demonstrate that PA-12 stimulates the pyruvate kinase activity of recombinant PKM2 in vitro, with a half-maximal activity concentration of 4.92 μM, and effectively suppresses both anchorage-dependent and -independent growth of lung cancer cells in non-essential amino acid-depleted medium. In addition, PA-12 blocked the nuclear translocalization of PKM2 in lung cancer cells, resulting in the inhibition of hypoxia response element (HRE)-mediated reporter activity as well as hypoxia-inducible factor 1 (HIF-1) target gene expression, eventually leading to the suppression of cell viability under hypoxia. We also verified that the effects of PA-12 were dependent on PKM2 expression in cancer cells, demonstrating the specificity of PA-12 for PKM2 protein. Taken together, our data suggest that PA-12 is a novel and potent PKM2 activator that has therapeutic implications for lung cancer.
authors: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 305-806, Korea.
authors: Dong Joon
authors: DJ
authors: Kim
authors: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 305-806, Korea.|Department of Functional Genomics, University of Science and Technology, Daejeon 305-350, Korea.
authors: Young Soo
authors: YS
authors: Park
authors: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 706-010, Korea.
authors: Nam Doo
authors: ND
authors: Kim
authors: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 706-010, Korea.
authors: Sang Hyun
authors: SH
authors: Min
authors: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 305-806, Korea.|Department of Functional Genomics, University of Science and Technology, Daejeon 305-350, Korea.
authors: Yeon-Mi
authors: YM
authors: You
authors: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 305-806, Korea.
authors: Yuri
authors: Y
authors: Jung
authors: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 305-806, Korea.|Department of Medical-BioScience, Soonchunhyang University, Asan 336-745, Korea.
authors: Han
authors: H
authors: Koo
authors: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 305-806, Korea.|Department of Functional Genomics, University of Science and Technology, Daejeon 305-350, Korea.
authors: Hanmi
authors: H
authors: Noh
authors: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 305-806, Korea.
authors: Jung-Ae
authors: JA
authors: Kim
authors: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 305-806, Korea.
authors: Kyung Chan
authors: KC
authors: Park
authors: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 305-806, Korea.|Department of Functional Genomics, University of Science and Technology, Daejeon 305-350, Korea.
authors: Young Il
authors: YI
authors: Yeom
mesh_terms: D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D008958:Models, Molecular; D010766:Phosphorylation; D011770:Pyruvate Kinase / Q000235:genetics* / Q000378:metabolism
chemical_list: D011770:Pyruvate Kinase
keywords: PA-12; PKM2 activator; hypoxia; lung cancer