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 TGFβ1-induced epithelial-mesenchymal transition (EMT) and metastasis of nasopharyngeal carcinoma (NPC).

MAIN METHODS

Fluorescent Bodipy fatty acid probe, UPLC-MS/MS analysis, β-oxidation assay, cellular ATP and NADPH/NADP measurement, and Oil Red-O staining were performed to evaluate the activation of FAO pathways in the TGFβ1-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 PGC1α-mediated FAO promotes TGFβ1-induced EMT and metastasis of NPC cells. Mechanically, TGFβ1 up-regulates AMPKα1 to activate PGC1α, which transcriptionally boosts FAO-associated genes. The metabolic rewiring mediated by PGC1α 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 PGC1α/ FAO signaling.