Lung cancer, notorious for its high mortality rates, is a leading cause of cancer-related deaths globally, with metastasis being the primary contributor to poor patient outcomes. A critical factor in this devastating disease is the metabolic reprogramming exhibited by cancer cells, particularly the preference for aerobic glycolysis over oxidative phosphorylation, a phenomenon known as the Warburg effect. This metabolic shift is central to cancer cell aggression and survival.
The current work delves into the role of ING5, a member of the ING tumor suppressor family, in regulating this metabolic reprogramming in lung cancer cells. The study uncovers a novel mechanism by which ING5 promotes the phosphorylation of pyruvate dehydrogenase kinase 1 (PDK1) at tyrosine 163 (Y163), thereby inhibiting the Warburg effect and reducing the malignancy of lung cancer cells. In this comprehensive analysis, the role of ING5 in lung cancer cell metabolism was investigated through a series of experiments, including phospho-proteomics, Western blot, and various cellular assays.
The results revealed that ING5 overexpression significantly increased PDK1 phosphorylation at Y163, which in turn negatively regulated PDK1 kinase activity towards pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1). This led to a decrease in PDHA1 S293 phosphorylation and an increase in PDH enzyme activity, promoting oxidative phosphorylation and reducing glycolysis. The clinical relevance of PDK1 Y163 phosphorylation was f.
