Inhibition of SREBP-1 Activation by a Novel Small-Molecule Inhibitor Enhances the Sensitivity of Hepatocellular Carcinoma Tissue to Radiofrequency Ablation

Abstract

Radiofrequency ablation (RFA) is an important strategy for treatment of advanced hepatocellular carcinoma (HCC). However, the prognostic indicators of RFA therapy are not known, and there are few strategies for RFA sensitization. The transcription factor sterol regulatory element binding protein 1 (SREBP)-1 regulates fatty-acid synthesis but also promotes the proliferation or metastasis of HCC cells. Here, the clinical importance of SREBP-1 and potential application of knockdown of SREBP-1 expression in RFA of advanced HCC was elucidated. In patients with advanced HCC receiving RFA, a high level of endogenous SREBP-1 expression correlated to poor survival. Inhibition of SREBP-1 activation using a novel small-molecule inhibitor, SI-1, not only inhibited the aerobic glycolysis of HCC cells, it also enhanced the antitumor effects of RFA on xenograft tumors. Overall, our results: (i) revealed the correlation between SREBP-1 and HCC severity; (ii) indicated that inhibition of SREBP-1 activation could be a promising approach for treatment of advanced HCC.

A Novel Small-Molecule Inhibitor of SREBP-1 Based on Natural Product Monomers Upregulates the Sensitivity of Lung Squamous Cell Carcinoma Cells to Antitumor Drugs

“…Although research and development of small molecule inhibitors of SREBP-1 is necessary, the number of existing inhibitors (such as fatostatin, FGH10019, betulin, and PF-429242) is small and the reports are few, and they have not entered clinical application ( Kamisuki et al, 2011 ; Zou et al, 2021b ; Wang T. B. et al, 2021 ; Ren et al, 2021 ). In addition to these, a recent report by Zou et al (2021) found a relationship between the expression level of SREBP-1 in HCC tissues and the prognosis of HCC RFA, and used a novel small molecule inhibitor of SREBP-1 in combination with RFA to achieve a better anti-tumor effect on HCC ( Trott and Olson, 2010 ).…”

Targeting SREBP-1-Mediated Lipogenesis as Potential Strategies for Cancer

“…N-Arachidonoyl dopamine, a typical representative of N-acyl dopamines, can inhibit breast cancer cell migration, EMT, and stemness and cause decreased cholesterol biosynthesis by inhibiting SREBP-1, its key targets, and endoplasmic reticulum kinase 1/2 (ERK1/2) pathways ( 151 ). A novel small-molecule, SI-1, 1-(4-bromophenyl)-3-(pyridin-3-yl) urea inhibits aerobic glycolysis and enhances the antitumor effect of radiofrequency ablation in the HCC cells and xenograft tumors via inhibition of SREBP-1 activation ( 152 ). The treatment of docosahexaenoic acid, but neither n-6 PUFA arachidonic acid nor oleic acid, can inhibit the levels of the precursor of SREBP-1 and its mature form, and FASN is induced by estradiol and insulin to mediate breast cancer proliferation, which is the result from reduced phosphorylated Akt, not from ERK1/2 phosphorylation ( 153 ).…”

A Single Nucleotide Mixture Enhances the Antitumor Activity of Molecular-Targeted Drugs Against Hepatocellular Carcinoma

“…Glucose administration to experimental animals affects the metabolic characteristics of HCC tissues and expression of proliferation-related factors ( Broadfield et al, 2021 ; Loong et al, 2021 ). Cellular metabolism of glucose and lipids is closely related, and important regulators such as the transcription factors sterol regulatory element-binding transcription factor 1 (SREBP-1) and SREBP-2 can also affect expression of glucose metabolism-related factors and cellular glucose metabolism ( Yin et al, 2019 ; Zou et al, 2021 ). Therefore, our results suggest that glucose (energy support) and a lipid emulsion (nutritional support) will improve the physical status of patients, but may also promote HCC in vivo .…”