Gankyrin drives metabolic reprogramming to promote tumorigenesis, metastasis and drug resistance through activating β-catenin/c-Myc signaling in human hepatocellular carcinoma. (28th February 2019)

• Record Type: Journal Article
• Authors: Liu, Ruiqi; Li, Yuejin; Tian, Lantian; Shi, Huawen; Wang, Jiabei; Liang, Yingjian; Sun, Boshi; Wang, Shuangjia; Zhou, Meng; Wu, Li; Nie, Jianhua; Lin, Binlin; Tang, Shuli; Zhang, Yanqiao; Wang, Guangyu; Zhang, Chunhui; Han, Jiguang; Xu, Benjie; Liu, Lianxin; Gong, Kunmei; Zheng, Tongsen
• Is Part Of: Cancer letters. Volume 443(2019)
• Page Start: 34
• Page End: 46
• Publication Date: 2019-02-28
• Subjects: Gankyrin -- Metabolic reprogramming -- c-Myc -- Tumorigenecity -- Drug resistance; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.11.030
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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 β-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 β-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 β-catenin/c-Myc to promotes tumorigenesis, metastasis and drug resistance in human HCC. Highlights: Gankyrin promotes glycolysis and glutaminolysis through activation of c-Myc via upregulating β-catenin in HCC. c-Myc-mediated metabolism reprogramming plays an important role in the stimulating effects of Gankyrin on HCC progression. Gankyrin/β-catenin combination is a powerful predictor for overall survival of HCC. Combination of c-Myc inhibitor and Sorafenib or Regorafenib could be a new treatment modality for HCC with high Gankyrin.