ING5 inhibits aerobic glycolysis of lung cancer cells by promoting TIE1-mediated phosphorylation of pyruvate dehydrogenase kinase 1 at Y163

Abstract

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.

Keywords

ING5 / aerobic glycolysis / PDK1 / phosphorylation / lung cancer / TIE1

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (Nos. 81672269, 81272587, and 81172223).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-024-1057-7 and is accessible for authorized users.

Compliance with ethics guidelines

Conflicts of interest Haihua Zhang, Xinli Liu, Junqiang Li, Jin Meng, Wan Huang, Xuan Su, Xutao Zhang, Guizhou Gao, Xiaodong Wang, Haichuan Su, Feng Zhang, and Tao Zhang declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The study was approved by the the Animal Care and Use Committee of Fourth Military Medical University (approval no: 20160505) and the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.. Informed consent was obtained from all patients for being included in the study.

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