ING5 inhibits aerobic glycolysis of lung cancer cells by promoting TIE1-mediated phosphorylation of pyruvate dehydrogenase kinase 1 at Y163
Haihua Zhang1, Xinli Liu2, Junqiang Li3, Jin Meng4, Wan Huang5, Xuan Su1, Xutao Zhang6, Guizhou Gao1, Xiaodong Wang1, Haichuan Su3(), Feng Zhang2(), Tao Zhang1()
. Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an 710038, China . Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an 710038, China . Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi’an 710038, China . Department of Pharmacy, the Medical Security Centre, Chinese PLA General Hospital, Beijing 100091, China . National Translational Science Center for Molecular Medicine and Department of Cell Biology, Fourth Military Medical University, Xi’an 710038, China . Aerospace Clinical Medical Center, School of Aerospace Medicine, Fourth Military Medical University, Xi’an 710038, China
Aerobic glycolysis is critical for tumor growth and metastasis. Previously, we have found that the overexpression of the inhibitor of growth 5 (ING5) inhibits lung cancer aggressiveness and epithelial–mesenchymal transition (EMT). However, whether ING5 regulates lung cancer metabolism reprogramming remains unknown. Here, by quantitative proteomics, we showed that ING5 differentially regulates protein phosphorylation and identified a new site (Y163) of the key glycolytic enzyme PDK1 whose phosphorylation was upregulated 13.847-fold. By clinical study, decreased p-PDK1Y163 was observed in lung cancer tissues and correlated with poor survival. p-PDK1Y163 represents the negative regulatory mechanism of PDK1 by causing PDHA1 dephosphorylation and activation, leading to switching from glycolysis to oxidative phosphorylation, with increasing oxygen consumption and decreasing lactate production. These effects could be impaired by PDK1Y163F mutation, which also impaired the inhibitory effects of ING5 on cancer cell EMT and invasiveness. Mouse xenograft models confirmed the indispensable role of p-PDK1Y163 in ING5-inhibited tumor growth and metastasis. By siRNA screening, ING5-upregulated TIE1 was identified as the upstream tyrosine protein kinase targeting PDK1Y163. TIE1 knockdown induced the dephosphorylation of PDK1Y163 and increased the migration and invasion of lung cancer cells. Collectively, ING5 overexpression—upregulated TIE1 phosphorylates PDK1Y163, which is critical for the inhibition of aerobic glycolysis and invasiveness of lung cancer cells.
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Haihua Zhang, Xinli Liu, Junqiang Li, Jin Meng, Wan Huang, Xuan Su, Xutao Zhang, Guizhou Gao, Xiaodong Wang, Haichuan Su, Feng Zhang, Tao Zhang. ING5 inhibits aerobic glycolysis of lung cancer cells by promoting TIE1-mediated phosphorylation of pyruvate dehydrogenase kinase 1 at Y163. Front. Med., 2024, 18(5): 878-895.
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