A Novel Pyruvate Kinase M2 Activator Compound that Suppresses Lung Cancer Cell Viability under Hypoxia

• Published in: Molecules and cells Vol. 38; no. 4; pp. 373 - 379
• Main Authors: Kim, D.J., Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea, Park, Y.S., Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea, Kim, N.D., Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu, Republic of Korea, Min, S.H., Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu, Republic of Korea, You, Y.M., Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea, Jung, Y., Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea, Koo, H., Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea, Noh, H., Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea, Kim, J.A., Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea, Park, K.C., Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea, Yeom, Y.I., Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
• Format: Journal Article
• Language: English
• Published: United States Korean Society for Molecular and Cellular Biology 01.04.2015; 한국분자세포생물학회
• Subjects: ANOXIA; ANOXIE; Cell Hypoxia - physiology; Cell Line, Tumor; Cell Proliferation - physiology; Cell Survival - physiology; Humans; lung cancer,PA-12,PKM2 activator; Lung Neoplasms - enzymology; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Models, Molecular; Phosphorylation; Pyruvate Kinase - genetics; Pyruvate Kinase - metabolism; 생물학; lung cancer; PA-12; hypoxia; PKM2 activator
• ISSN: 1016-8478; 0219-1032
• DOI: 10.14348/molcells.2015.2314

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 micrometer, 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.