Journal Article

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

Wang, Lei, Cao, Yu, Li, Zongwei, Wang, Xiaoning, Yin, Fan, Feng, Fan

2019

Overview

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.

• Publisher: Nature Publishing Group UK,Springer Nature B.V
• Subject: 13 / 13/1 / 13/109 / 13/2 / 13/89 / 14 / 14/63 / 38 / 38/77 / 59 / 631/45 / 631/67 / 631/80 / Animals / Antibodies / Antineoplastic Combined Chemotherapy Protocols - pharmacology / Antineoplastic Combined Chemotherapy Protocols - toxicity / Antitumor activity / Biochemistry / Biomedical and Life Sciences / Carcinoma, Hepatocellular - drug therapy / Carcinoma, Hepatocellular - metabolism / Carcinoma, Hepatocellular - mortality / Carcinoma, Hepatocellular - pathology / Cell Biology / Cell Culture / Cell Movement - drug effects / Cell Movement - genetics / Cell proliferation / Cell Proliferation - drug effects / Cell Proliferation - genetics / Drug Synergism / Gene Expression Regulation, Neoplastic - drug effects / Gene Expression Regulation, Neoplastic - genetics / Glucose metabolism / Glycolysis / Glycolysis - drug effects / Glycolysis - genetics / Hep G2 Cells / Hepatocellular carcinoma / Humans / Immunology / Inhibitor drugs / Life Sciences / Lipid metabolism / Lipid Metabolism - drug effects / Lipid Metabolism - genetics / Liver cancer / Liver Neoplasms - drug therapy / Liver Neoplasms - metabolism / Liver Neoplasms - mortality / Liver Neoplasms - pathology / Medical prognosis / Metabolism / Metastases / Mice / Mice, Nude / Prognosis / Sorafenib - pharmacology / Sorafenib - therapeutic use / Sterol Regulatory Element Binding Protein 1 - antagonists & inhibitors / Sterol Regulatory Element Binding Protein 1 - genetics / Sterol Regulatory Element Binding Protein 1 - metabolism / Sterol regulatory element-binding protein / Targeted cancer therapy / Transplantation, Heterologous / Triterpenes - pharmacology / Triterpenes - therapeutic use / Xenografts