IGF1-PGM5 Axis Suppresses Nasopharyngeal Carcinoma Progression by Inhibiting Aerobic Glycolysis

Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with a distinct geographical distribution, often associated with high rates of distant metastasis and poor prognosis despite conventional therapies. This underscores a critical need for novel therapeutic strategies. Aerobic glycolysis, also known as the Warburg effect, is a metabolic hallmark of many cancers, fueling rapid proliferation and survival. Understanding and targeting these altered metabolic pathways, particularly in NPC, represents a promising avenue for intervention, especially when considering the limitations of current standard-of-care treatments.

Researchers performed integrated transcriptomic analysis on Gene Expression Omnibus datasets to identify core glycolysis-related genes in NPC. Machine learning algorithms screened differentially expressed genes. The tumor-suppressive function of insulin-like growth factor 1 (IGF1) was demonstrated through a combination of in vitro assays, assessing proliferation, migration, invasion, apoptosis, and glycolysis. These findings were then validated in in vivo xenograft models. Co-immunoprecipitation examined the IGF1-PGM5 interaction, while Western blotting measured IGF1R and p-IGF1R levels. PGM5 involvement was confirmed via knockdown rescue experiments.

IGF1 was identified as a significantly downregulated core gene in NPC. Its overexpression inhibited NPC cell proliferation, migration, and invasion, while promoting apoptosis. These findings were corroborated in vivo. Notably, Co-immunoprecipitation revealed a direct physical interaction between IGF1 and PGM5. > IGF1 overexpression suppressed glycolysis, evidenced by reduced glucose consumption, lactate production, and decreased expression of key glycolytic enzymes hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA). Crucially, IGF1 overexpression did not alter total IGF1R or p-IGF1R levels, indicating an IGF1R-independent mechanism. IGF1 positively correlated with PGM5, and PGM5 knockdown attenuated IGF1's tumor-suppressive and glycolytic-inhibitory effects, confirming PGM5 as a critical mediator in this novel IGF1-dependent metabolic regulatory pathway.