ING5 regulates metabolic reprogramming in lung cancer cells

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 further established through immunohistochemical staining of tumor tissue microarrays, showing that higher levels of this phosphorylation were associated with better prognosis in lung cancer patients.

The study also explored the impact of PDK1 Y163 phosphorylation on lung cancer cell proliferation, invasion, and metabolism. It was found that a phospho-dead mutation at Y163 abolished the inhibitory effects of ING5 overexpression on these cellular processes. Furthermore, in vivo experiments using mouse xenograft models confirmed that ING5 overexpression inhibited tumor growth and metastasis, effects that were reversed by the Y163F mutation. These findings underscore the importance of PDK1 Y163 phosphorylation in lung cancer progression and its potential as a therapeutic target.

In a search for the kinase responsible for PDK1 Y163 phosphorylation, TIE1 was identified as a potential candidate. TIE1, a receptor tyrosine kinase, was found to be upregulated by ING5 and capable of directly phosphorylating PDK1 at Y163. The study demonstrated that TIE1 localized to the mitochondria and its knockdown reduced PDK1 Y163 phosphorylation, further implicating TIE1 in the ING5-mediated metabolic reprogramming of lung cancer cells.

In conclusion, this work has identified a novel signaling pathway involving ING5, TIE1, and PDK1 Y163 phosphorylation that plays a crucial role in regulating the metabolic reprogramming and aggressiveness of lung cancer cells. The findings suggest that targeting this pathway, particularly through the promotion of PDK1 Y163 phosphorylation, may offer a promising therapeutic strategy for lung cancer treatment. The study's contributions to understanding the molecular mechanisms underlying lung cancer metabolism and invasion highlight the potential of precision medicine approaches in combating this deadly disease.