有氧糖酵解对于肿瘤生长和转移至关重要。此前，我们发现生长抑制剂5（ING5）的过度表达可抑制肺癌侵袭性和上皮间质转化（EMT）。然而，ING5是否调节肺癌代谢重编程仍不清楚。在这里，通过定量蛋白质组学，我们发现 ING5 差异调节蛋白质磷酸化，并鉴定了关键糖酵解酶 PDK1 的一个新位点（Y163），其磷酸化上调了 13.847 倍。通过临床研究，在肺癌组织中观察到 p-PDK1Y163 减少，并且与生存率较差相关。 p-PDK1Y163 代表 PDK1 的负调节机制，通过引起 PDHA1 去磷酸化和激活，导致从糖酵解转变为氧化磷酸化，从而增加耗氧量并减少乳酸产生。这些作用可能会因 PDK1Y163F 突变而受损，这也会损害 ING5 对癌细胞 EMT 和侵袭性的抑制作用。小鼠异种移植模型证实了 p-PDK1Y163 在 ING5 抑制肿瘤生长和转移中不可或缺的作用。通过siRNA筛选，ING5上调的TIE1被鉴定为靶向PDK1Y163的上游酪氨酸蛋白激酶。 TIE1敲低诱导PDK1Y163去磷酸化并增加肺癌细胞的迁移和侵袭。总的来说，ING5 过表达上调的 TIE1 磷酸化 PDK1Y163，这对于抑制肺癌细胞的有氧糖酵解和侵袭性至关重要。© 2024。高等教育出版社。

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.© 2024. Higher Education Press.