HIF-1α switches the functionality of TGF-β signaling via changing the partners of smads to drive glucose metabolic reprogramming in non-small cell lung cancer

Journal of Experimental & Clinical Cancer Research

Yuansheng Zheng¹  Zhencong Chen¹  Tao Lu¹  Ming Li¹  Jiacheng Yin¹  Cheng Zhan¹  Zongwu Lin¹  Junjie Xi¹  Wei Jiang¹  Yiwei Huang¹  Qun Wang¹  Zhengyang Hu¹  Jiaqi Liang¹  Guoshu Bi¹  Lijie Tan¹ 

[1] Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, 200032, Shanghai, China;

关键词: TGF-β/Smad signaling pathway;    HIF-1α;    Metabolic reprogramming;    Cell cycle;   

DOI  :  10.1186/s13046-021-02188-y

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY