Abstract
BackgroundMost cancer cells have fundamentally different metabolic characteristics, particularly much higher glycolysis rates than normal tissues, which support the increased demand for biosynthesis and promote tumor progression. We found that transforming growth factor (TGF)-β plays a dual function in regulating glycolysis and cell proliferation in non-small cell lung cancer.MethodsWe used the PET/MRI imaging system to observe the glucose metabolism of subcutaneous tumors in nude mice. Energy metabolism of non-small cell lung cancer cell lines detected by the Seahorse XFe96 cell outflow analyzer. Co-immunoprecipitation assays were used to detect the binding of Smads and HIF-1α. Western blotting and qRT-PCR were used to detect the regulatory effects of TGF-β and HIF-1α on c-MYC, PKM1/2, and cell cycle-related genes.ResultsWe discovered that TGF-β could inhibit glycolysis under normoxia while significantly promoting tumor cells’ glycolysis under hypoxia in vitro and in vivo. The binding of hypoxia-inducible factor (HIF)-1α to the MH2 domain of phosphorylated Smad3 switched TGF-β function to glycolysis by changing Smad partners under hypoxia. The Smad-p107-E2F4/5 complex that initially inhibited c-Myc expression was transformed into a Smad-HIF-1α complex that promoted the expression of c-Myc. The increased expression of c-Myc promoted alternative splicing of PKM to PKM2, resulting in the metabolic reprogramming of tumor cells. In addition, the TGF-β/Smad signal lost its effect on cell cycle regulatory protein p15/p21. Furthermore, high expression of c-Myc inhibited p15/p21 and promoted the proliferation of tumor cells under hypoxia.ConclusionsOur results indicated that HIF-1α functions as a critical factor in the dual role of TGF-β in tumor cells, and may be used as a biomarker or therapeutic target for TGF-β mediated cancer progression.
Highlights
Most cancer cells have fundamentally different metabolic characteristics, much higher glycolysis rates than normal tissues, which support the increased demand for biosynthesis and promote tumor progression
Our results indicated that hypoxia-inducible factor -1α (HIF-1α) functions as a critical factor in the dual role of transforming growth factor -β (TGF-β) in tumor cells, and may be used as a biomarker or therapeutic target for transforming growth factor (TGF)-β mediated cancer progression
TGF‐β plays a dual function in regulating the glucose metabolism of non-small cell lung cancer (NSCLC) under normoxia and hypoxia By analyzing the Cancer Genome Atlas (TCGA) database data, we found that TGF-β and hypoxia-inducible factor (HIF)-1α were significantly overexpressed in patients with high glycolysis scores
Summary
Most cancer cells have fundamentally different metabolic characteristics, much higher glycolysis rates than normal tissues, which support the increased demand for biosynthesis and promote tumor progression. We found that transforming growth factor (TGF)-β plays a dual function in regulating glycolysis and cell proliferation in non-small cell lung cancer. In normal epithelial cells and early tumor cells, TGF-β usually inhibits cell proliferation by regulating cell cycle-related genes. Studies have revealed that this is due to the mutation of key signaling molecules in the process of TGF-β signal transduction, leading to a loss of its antitumor effects in tumor cells [8, 9]. In tumor cells with an intact TGF-β signaling pathway, it was found that TGF-β could still promote tumor progression. It is believed that the Smad partners change during TGF-β signaling, leading to loss of the original inhibitory function of TGF-β against specific genes that promote tumor progression [6, 10]
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