TY - JOUR
T1 - Combined inhibition of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase a induces metabolic and signaling reprogramming and enhances lung adenocarcinoma cell killing
AU - Zhou, Yan
AU - Guo, Yizhen
AU - Ran, Maoxin
AU - Shan, Wenying
AU - Granchi, Carlotta
AU - Giovannetti, Elisa
AU - Minutolo, Filippo
AU - Peters, Godefridus J.
AU - Tam, Kin Yip
N1 - Funding Information: We thank Prof. Guokai Chen (FHS, University of Macau) for a sample of the human fibroblast cell line and the technical support from Animal Research Core and Biological Imaging & Stem Cell Core at Faculty of Heath Sciences, University of Macau. This work was financially supported by University of Macau (grant no. MYRG2019-00034-FHS ), the Science and Technology Development Fund, Macau SAR (File no. 0138/2022/A). Publisher Copyright: © 2023 Elsevier B.V.
PY - 2023/11/28
Y1 - 2023/11/28
N2 - Lung adenocarcinoma (LUAD) is one of the most prevalent and aggressive types of lung cancer. Metabolic reprogramming plays a critical role in the development and progression of LUAD. Pyruvate dehydrogenase kinase 1 (PDK1) and lactate dehydrogenase A (LDHA) are two key enzymes involved in glucose metabolism, whilst their aberrant expressions are often associated with tumorigenesis. Herein, we investigated the anticancer effects of combined inhibition of PDK1 and LDHA in LUAD in vitro and in vivo and its underlying mechanisms of action. The combination of a PDK1 inhibitor, 64, and a LDHA inhibitor, NHI-Glc-2, led to a synergistic growth inhibition in 3 different LUAD cell lines and more than additively suppressed tumor growth in the LUAD xenograft H1975 model. This combination also inhibited cellular migration and colony formation, while it induced a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) resulting in mitochondrial depolarization and apoptosis in LUAD cells. These effects were related to modulation of multiple cell signaling pathways, including AMPK, RAS/ERK, and AKT/mTOR. Our findings demonstrate that simultaneous inhibition of multiple glycolytic enzymes (PDK1 and LDHA) is a promising novel therapeutic approach for LUAD.
AB - Lung adenocarcinoma (LUAD) is one of the most prevalent and aggressive types of lung cancer. Metabolic reprogramming plays a critical role in the development and progression of LUAD. Pyruvate dehydrogenase kinase 1 (PDK1) and lactate dehydrogenase A (LDHA) are two key enzymes involved in glucose metabolism, whilst their aberrant expressions are often associated with tumorigenesis. Herein, we investigated the anticancer effects of combined inhibition of PDK1 and LDHA in LUAD in vitro and in vivo and its underlying mechanisms of action. The combination of a PDK1 inhibitor, 64, and a LDHA inhibitor, NHI-Glc-2, led to a synergistic growth inhibition in 3 different LUAD cell lines and more than additively suppressed tumor growth in the LUAD xenograft H1975 model. This combination also inhibited cellular migration and colony formation, while it induced a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) resulting in mitochondrial depolarization and apoptosis in LUAD cells. These effects were related to modulation of multiple cell signaling pathways, including AMPK, RAS/ERK, and AKT/mTOR. Our findings demonstrate that simultaneous inhibition of multiple glycolytic enzymes (PDK1 and LDHA) is a promising novel therapeutic approach for LUAD.
KW - Anticancer
KW - Combination treatment
KW - Non-small cell lung cancer
KW - Warburg effect
UR - http://www.scopus.com/inward/record.url?scp=85174047173&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.canlet.2023.216425
DO - https://doi.org/10.1016/j.canlet.2023.216425
M3 - Article
C2 - 37805163
SN - 0304-3835
VL - 577
JO - Cancer Letters
JF - Cancer Letters
M1 - 216425
ER -