Abstract
Metabolic reprogramming is a hallmark of malignancy. Testes-specific protease 50 (TSP50), a newly identified oncogene, has been shown to play an important role in tumorigenesis. However, its role in tumor cell metabolism remains unclear. To investigate this issue, LC–MS/MS was employed to identify TSP50-binding proteins and pyruvate kinase M2 isoform (PKM2), a known key enzyme of aerobic glycolysis, was identified as a novel binding partner of TSP50. Further studies suggested that TSP50 promoted aerobic glycolysis in HCC cells by maintaining low pyruvate kinase activity of the PKM2. Mechanistically, TSP50 promoted the Warburg effect by increasing PKM2 K433 acetylation level and PKM2 acetylation site (K433R) mutation remarkably abrogated the TSP50-induced aerobic glycolysis, cell proliferation in vitro and tumor formation in vivo. Our findings indicate that TSP50-mediated low PKM2 pyruvate kinase activity is an important determinant for Warburg effect in HCC cells and provide a mechanistic link between TSP50 and tumor metabolism.
Highlights
In the presence of sufficient levels of oxygen, normal quiescent cells metabolize glucose to pyruvate, which is further oxidized through oxidative phosphorylation to generate ATP for cellular processes while more glucose is metabolized into lactate under hypoxic conditions
We demonstrated that Testes-specific protease 50 (TSP50) maintained the low pyruvate kinase activity of pyruvate kinase M2 isoform (PKM2) by directly mediating the acetylation of PKM2 at K433
TSP50 is highly expressed in hepatocellular carcinoma (HCC) and survival-associated We evaluated TSP50 transcription levels via UALCAN
Summary
In the presence of sufficient levels of oxygen, normal quiescent cells metabolize glucose to pyruvate, which is further oxidized through oxidative phosphorylation to generate ATP for cellular processes while more glucose is metabolized into lactate under hypoxic conditions. Even in the presence of sufficient oxygen, tumor cells can reconstruct the process of glucose metabolism, limiting energy metabolism largely to glycolysis, which is called aerobic glycolysis or Warburg effect[1,2]. This cell metabolism reprogramming allows tumor cells to maintain the balance between energy demand and synthetic. Interfering with the metabolic changes of tumor cells reduces tumorigenicity and increases apoptosis sensitivity to chemotherapeutic drugs, indicating that aerobic glycolysis metabolism is a key metabolic factor for tumor development[12,13,14,15]. TSP50 is Official journal of the Cell Death Differentiation Association
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