TGF-βRII regulates glucose metabolism in oral cancer-associated fibroblasts via promoting PKM2 nuclear translocation

Cancer-associated fibroblasts (CAFs) are highly heterogeneous and differentiated stromal cells that promote tumor progression via remodeling of extracellular matrix, maintenance of stemness, angiogenesis, and modulation of tumor metabolism. Aerobic glycolysis is characterized by an increased uptake of glucose for conversion into lactate under sufficient oxygen conditions, and this metabolic process occurs at the site of energy exchange between CAFs and cancer cells. As a hallmark of cancer, metabolic reprogramming of CAFs is defined as reverse Warburg effect (RWE), characterized by increased lactate, glutamine, and pyruvate, etc. derived from aerobic glycolysis. Given that the TGF-beta signal cascade plays a critical role in RWE mainly through metabolic reprogramming related proteins including pyruvate kinase muscle isozyme 2 (PKM2), however, the role of nuclear PKM2 in modifying glycolysis remains largely unknown. In this study, using a series of in vitro and in vivo experiments, we provide evidence that TGF-beta RII overexpression suppresses glucose metabolism in CAFs by attenuating PKM2 nuclear translocation, thereby inhibiting oral cancer tumor growth. This study highlights a novel pathway that explains the role of TGF-beta RII in CAFs glucose metabolism and suggests that targeting TGF-beta RII in CAFs might represent a therapeutic approach for oral cancer.

Automated summary

This study reveals that TGF-beta RII overexpression can suppress glucose metabolism in CAFs by attenuating PKM2 nuclear translocation, thereby inhibiting oral cancer tumor growth, providing a novel therapeutic approach for oral cancer treatment.