PGC1α-mediated fatty acid oxidation promotes TGFβ1-induced epithelial-mesenchymal transition and metastasis of nasopharyngeal carcinoma

Aim: Cancer cells frequently undergo metabolic reprogramming, which contributes to tumorigenicity and malignancy. Unlike primary cancers, during the process of invasion and distal dissemination, cancer cells are deficient in ATP due to damaged glucose transport. Cells need to rewire metabolic programs to overcome nutrient and energy crises, maintaining survival and forming metastasis. However, the underlying mechanism has not been well understood. We elucidated the metabolic alteration in TGF beta 1-induced epithelial-mesenchymal transition (EMT) and metastasis of nasopharyngeal carcinoma (NPC). Main methods: Fluorescent Bodipy fatty acid probe, UPLC-MS/MS analysis, beta-oxidation assay, cellular ATP and NADPH/NADP measurement, and Oil Red-O staining were performed to evaluate the activation of FAO pathways in the TGF beta 1-induced EMT of NPC cells. Three-dimensional (3D) invasion assay and metastatic animal model were applied to assess the invasive and metastatic capacity of NPC cells. Key findings: Our current findings reveal that PGC1 alpha-mediated FAO promotes TGF beta 1-induced EMT and metastasis of NPC cells. Mechanically, TGF beta 1 up-regulates AMPK alpha 1 to activate PGC1 alpha, which transcriptionally boosts FAO associated genes. The metabolic rewiring mediated by PGC1 alpha facilitates EMT, invasion, and metastasis of NPC. Significance: The present study aims to establish the mechanistic connection between energy metabolic reprogramming and the aggressive phenotype of NPC. These actions further provide new opportunities for developing of novel therapeutics for NPC by targeting PGC1 alpha/ FAO signaling.

Automated summary

This study elucidated the metabolic alteration in TGF-beta 1-induced EMT and metastasis of NPC cells, and found that PGC1 alpha-mediated FAO promotes EMT and metastasis of NPC cells. This study is of great significance for understanding the mechanistic connection between energy metabolic reprogramming and the aggressive phenotype of NPC.