SREBP-1 inhibitor Betulin enhances the antitumor effect of Sorafenib on hepatocellular carcinoma via restricting cellular glycolytic activity

  • Cell Death Dis. 2019 Sep 11;10(9):672. doi: 10.1038/s41419-019-1884-7.
Fan Yin  1 ,  Fan Feng  2 ,  Lei Wang  3 ,  Xiaoning Wang  4 ,  Zongwei Li  3 ,  Yu Cao  5
Affiliations
  • 1. Department of Oncology, the Second Medical Centre & National Clinical Research Center of Geriatric Disease, Chinese PLA General Hospital, 100853, Beijing, People's Republic of China. [email protected].
  • 2. Center for Clinical Laboratory, the Fifth Medical Centre, Chinese PLA General Hospital, 100039, Beijing, People's Republic of China.
  • 3. Department of Gastroenterology, the First Medical Centre, Chinese PLA General Hospital, 100843, Beijing, People's Republic of China.
  • 4. Department of Blood Transfusion, the First Hospital of Jilin University, Changchun, 130021, Jilin Province, People's Republic of China.
  • 5. Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, 33612, Tampa, FL, USA. [email protected].
PMID: 31511501 DOI: 10.1038/s41419-019-1884-7
Abstract

Lipid metabolism that correlates tightly to the glucose metabolic regulation in malignant cells includes hepatocellular carcinoma (HCC) cells. The transcription factor Sterol Regulatory Element Binding Protein 1 (SREBP-1), a regulator of fatty acid synthesis, has been shown to pivotally regulate the proliferation and metastasis of HCC cells. However, the intrinsic mechanism by which SREBP-1 regulates the survival of HCC cells remains unclear. In this study, among HCC patients who had dismal responses to Sorafenib, a high SREBP-1 level was found in the tumors and correlated to poor survival. This observation suggested the negative role of SREBP-1 in clinical HCC prognosis. Our mechanistical studies reveal that the inhibition of SREBP-1 via its inhibitor Betulin suppresses cellular glucose metabolism. In addition to the reduced glycolytic activity, a thwarted metastatic potential was observed in HCC cells upon Betulin administration. Moreover, our data show that SREBP-1 inhibition facilitated the antitumor effects of Sorafenib on HCC cells and xenograft tumors.

Products