Journal
CANCER LETTERS
Volume 443, Issue -, Pages 34-46Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2018.11.030
Keywords
Gankyrin; Metabolic reprogramming; c-Myc; Tumorigenecity; Drug resistance
Categories
Funding
- National Natural Scientific Foundation of China [81472322, 81872435, 81672930]
- national youth talent support program
- China Postdoctoral Science Foundation [2015T80369, 2014M560271]
- Heilongjiang Postdoctoral Science Foundation [LBH-Z14142, LBH-Z16153, LBH-TZ1615]
- Fok Ying Tung Education Foundation [151037]
- Scientific research project of the health planning committee of Heilongjiang [2017130]
- Academician Yu Weihan Outstanding youth foundation of Harbin Medical University
- Natural Science Foundation of Heilongjiang Province [LC201437/H1617]
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Gankyrin plays important roles in tumorigenicity and metastasis of hepatocellular carcinoma (HCC). We have for the first time investigated the effects of Gankyrin on glycolysis and glutaminolysis both in vitro and in vivo, including in patient-derived xenografts. We reported Gankyrin increases glucose consumption, lactate production, glutamine consumption and glutamate production in HCC through upregulating the expression of the transporters and enzymes involved in glycolysis and glutaminolysis, including HK2, GLUT1, LDHA, PKM2, ASCT2 and GLS1. We further demonstrated that Gankyrin drives glycolysis and glutaminolysis through upregulating c-Myc via activating beta-catenin signaling. Importantly, we found c-Myc mediated metabolic reprogramming might contribute to the tumorigenicity, metastasis and drug resistance induced by Gankyrin. c-Myc inhibitor synergizes with Sorafenib or Regorafenib to suppress HCC PDX tumors with high Gankyrin levels. We detected a significant correlation between Gankyrin and beta-catenin expression levels in a cohort of HCC biopsies, and combination of these two parameters is a more powerful predictor of poor prognosis. Collectively, our results uncovered that Gankyrin functions as an essential regulator in glycolysis and glutaminolysis via activation of beta-catenin/c-Myc to promotes tumorigenesis, metastasis and drug resistance in human HCC.
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