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

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

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.

Highlights

Introduction InChina, the population of chronic asymptomaticHepatitis B Virus (HBV) infection-associated patients exceeds 80 million[1,2,3]
The expression of Sterol Regulatory Element Binding Protein 1 (SREBP-1) in 52 fine-needle aspiration tumor specimens derived from Hepatocellular carcinoma (HCC) patients who received Sorafenib treatment was measured and analyzed
By testing the transcription level of the key genes in metabolism pathways, we found that Betulin treatment reduced the expression of lipid metabolism-associated genes, including acetyl-CoA carboxylation (ACC), ATP citrate lyase (ACLY), fatty acid synthase (FASN), and acylCoA synthetase (ACS) as expected (Fig. 2e, Supplementary Fig. 6 and Supplementary Table 5)

Summary

Introduction

Introduction InChina, the population of chronic asymptomaticHepatitis B Virus (HBV) infection-associated patients exceeds 80 million[1,2,3]. Hepatocellular carcinoma (HCC) is the final malignant disease developed from liver lesions such as HBV infection; it is a fatal threat to life and an increasing burden to the public medical service[4,5,6]. Kinase inhibitors represented by Sorafenib are the major treatment choice for advanced HCC patients[7,8]. The randomized controlled phase III trials, represented by the SHARP (Sorafenib HCC Assessment Randomized Protocol) clinical trial, have shown that Sorafenib significantly prolongs the median survival of patients compared with the placebo group, making it a first-line antitumor agent for advanced HCC treatment[12,13,14,15]. The sensitivity of Sorafenib in HCC patients varies, with a large proportion developed for Sorafenib resistance unexpectedly[16,17]. It is of great importance to discover a new drug and/or to develop a novel therapeutic strategy that increases the efficacy of Sorafenib

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Results

Conclusion