p110α Hot Spot Mutations E545K and H1047R Exert Metabolic Reprogramming Independently of p110α Kinase Activity

Area of Science:

• Biochemistry
• Oncology
• Metabolic studies

Background:

• The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit p110α is frequently mutated in human cancers.
• Hot spot mutations (E542K, E545K, H1047R) are common in p110α, but their in vivo metabolic consequences remain largely unknown.
• Understanding these mutations' effects is crucial for cancer metabolism research.

Purpose of the Study:

• To investigate the in vivo effects of p110α hot spot mutations (E545K and H1047R) on hepatic and whole-body glucose metabolism.
• To elucidate the metabolic reprogramming induced by these specific PI3K mutations.

Main Methods:

• Adenoviral gene transfer was employed in mice to express mutant p110α (E545K and H1047R).
• Hepatic and whole-body glucose metabolism were assessed.
• Lipid and glycogen accumulation, glycolysis, and lipogenic gene expression were analyzed.

Main Results:

• Expression of mutant p110α (E545K, H1047R) rapidly induced hepatic steatosis (fatty liver) and marked glycogen accumulation.
• Mutant p110α expression paradoxically led to increased glucose tolerance.
• Wild-type p110α expression did not cause these metabolic alterations, despite similar upregulation of glycolysis and lipogenic genes.
• The metabolic reprogramming by mutants was independent of PI3K lipid kinase activity.

Conclusions:

• Specific hot spot mutations in p110α significantly reprogram hepatic metabolism in vivo.
• These PI3K mutations induce steatosis and alter glucose metabolism independently of their canonical lipid kinase function.
• Findings provide novel insights into the non-canonical roles of mutated PI3K in cancer metabolism.