PPP2R2C promotes aerobic glycolysis and mediates pemetrexed resistance in lung adenocarcinomas by upregulating TCP1-dependent protein folding of glycolytic enzymes.

Lung adenocarcinoma (LUAD) remains lethal primarily due to its tendency for early metastasis and the universal development of chemotherapy resistance. The results of this study delineate a coherent signaling axis, originating from the upregulation of PPP2R2C expression to metabolic reprogramming, which ultimately influences the malignant progression and chemotherapy resistance of LUAD. GEPIA analysis was used to evaluate PPP2R2C expression in NSCLC. Following shRNA-mediated knockdown, cell proliferation, migration, apoptosis, and glycolytic activity were assessed in NCI-H1299 and A549 cells. Subcutaneous tumor formation was evaluated four weeks after injection of LV-shPPP2R2C or control vector, followed by H&E staining and immunohistochemical analysis of PPP2R2C and Ki67. Clinical analysis shows that PPP2R2C is highly expressed in LUAD and is associated with poor prognosis, lymph node metastasis, and advanced disease stage. In vitro knockdown of PPP2R2C suppresses proliferation and migration and promotes apoptosis. Mechanistically, PPP2R2C drives the Warburg effect by upregulating the molecular chaperone TCP1 to ensure proper folding of glycolytic enzymes. Blocking TCP1 or glycolysis (with 2-DG) reverses PPP2R2C-mediated survival advantage and pemetrexed resistance. In vivo experiments confirm that knocking down PPP2R2C or TCP1 similarly inhibits tumor growth and restores chemotherapy sensitivity. In summary, the results elucidate a novel mechanism whereby PPP2R2C enhances glycolysis by regulating TCP1-dependent protein refolding, thereby driving LUAD progression and chemoresistance. Thus, this study establishes a strong rationale for targeting this pathway as a potential therapeutic approach.