Abstract
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-β 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-βRII 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-βRII in CAFs glucose metabolism and suggests that targeting TGF-βRII in CAFs might represent a therapeutic approach for oral cancer.
Highlights
As the 1st or 2nd worldwide cause of death of individuals 70 years of age and younger in 112 of 183 countries, cancer was responsible for 10.0 million deaths globally in 2020 [1]
We found that the top ten glycolysis proteins related to the TGF-β signaling pathway included enolase 1 (ENO1), hexokinase 2 (HK2), hexokinase 1 (HK1), pyruvate kinase muscle isozyme 2 (PKM2), bisphosphoglycerate mutase (BPGM), tissues, well-differentiated oral SCC (OSCC) tissues, mild-to-poorly differentiated aldo-keto reductase family 1 member A1 (AKR1A1), phosphoeOSCC tissues, whereas PKM2 and HIF-1α expression exhibited the nolpyruvate carboxykinase 2 (PCK2), galactose mutarotase opposite patterns (Fig. 1A)
Increased glucose in the cellular microenvironment upregulated the expression of TGFβRI and TGF-βRII, subsequently leading to cell hypertrophy via TGF-β signaling pathway-mediated glucose metabolism [19]
Summary
As the 1st or 2nd worldwide cause of death of individuals 70 years of age and younger in 112 of 183 countries, cancer was responsible for 10.0 million deaths globally in 2020 [1]. Of note, CAFmediated glycolytic metabolism provides energy and degrades acid products in the surrounding environment to promote tumor cell survival in various cancers, such as lung [5], prostate [7], ovarian [8], and oral cancers [9]. To define the role of TGF-beta receptor type-2 (TGF-βRII) in squamous cell carcinoma (SCC), several mouse models with TGF-βRII deletions have been established. Lu et al found that TGF-βRII loss in oral keratinocytes was not an SCC initiation event [13]. Lu et al found that TGF-βRII loss in head and neck cancer was a common event [13], TGF-βRII and its role in oral CAF-mediated metabolic reprogramming have remained largely unknown during the past decade
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