SREBP2 inhibitor betulin sensitizes hepatocellular carcinoma to lenvatinib by inhibiting the mTOR/IL-1βpathway  

作　　者：Minghao Fan Zhenmei Chen Weiqing Shao Yiran Chen Zhifei Lin Chenhe Yi Yitong Li Lu Lu Yu Zhou Jing Lin 

机构地区：[1]Department of General Surgery,Huashan Hospital,Fudan University,Shanghai 200040,China [2]Department of Infectious Diseases,the Third Afflicted Hospital of Wenzhou Medical University,Wenzhou 325200,China

出　　处：《Acta Biochimica et Biophysica Sinica》2023年第9期1479-1486,共8页生物化学与生物物理学报（英文版）

基　　金：supported by the grants from the Zhejiang Provincial Natural Science Foundation of China(No.LY21H160009);the Zhejiang Provincial Medical and Health Science and Technology Project(No.2020KY927);the National Natural Science Foundation of China(No.82000605).

摘　　要：Lenvatinib has become the first-line therapy in advanced hepatocellular carcinoma(HCC),but its efficacy is still limited because of the inevitable development of resistance.It has been reported that cellular cholesterol levels are associated with tyrosine kinase inhibitor(TKI)efficacy.Here,we show that betulin,a sterol regulatory elementbinding protein 2(SREBP2)inhibitor,markedly enhances the anti-tumor effect of lenvatinib in HCC both in vitro and in vivo.Our results also show that the combination treatment of lenvatinib and betulin synergistically inhibits the proliferation and clonogenicity of HCC cells.The mRNA and protein expressions of IL-1βare markedly decreased in HCC cells treated with betulin,while the sensitivity of HCC cells to lenvatinib is enhanced.Moreover,we find that the knockdown of IL-1βalso enhances the efficacy of lenvatinib,and recombinant IL-1βprotein rescues cell viability,which is reduced by lenvatinib in HCC cells.Further mechanistic studies indicate that betulin decreases the level of IL-1βin HCC cells by inhibiting the mTOR signaling pathway.Finally,the growth of the tumors in xenograft mouse models subjected to combination treatment is significantly suppressed.In summary,our study reveals that the SREBP2 inhibitor betulin sensitizes hepatocellular carcinoma to lenvatinib by inhibiting the mTOR/IL-1βpathway,which may be a promising therapeutic strategy for patients with HCC.

关 键 词：hepatocellular carcinoma SREBP2 lenvatinib BETULIN CHOLESTEROL INTERLEUKIN-1Β 

分 类 号：R73[医药卫生—肿瘤]