SREBP2 inhibitor betulin sensitizes hepatocellular carcinoma to lenvatinib by inhibiting the mTOR/IL-1β pathway.
SREBP2 inhibitor betulin sensitizes hepatocellular carcinoma to lenvatinib by inhibiting the mTOR/IL-1β pathway.
复制标题
DOI：
10.3724/abbs.2023122
复制
发表时间：
2023-07-11
影响因子：
3.7
通讯作者：
Lin J
中科院分区：
文献类型：
--
作者：
Fan M;Chen Z;Shao W;Chen Y;Lin Z;Yi C;Li Y;Lu L;Zhou Y;Lin J
乐伐替尼已成为晚期肝细胞癌（HCC）的一线治疗药物，但由于不可避免的耐药性，其疗效仍然有限。据报道，细胞胆固醇水平与酪氨酸激酶抑制剂（TKI）功效相关。在这里，我们发现桦木醇（一种甾醇调节元件结合蛋白2（SREBP2）抑制剂）在体外和体内均显着增强乐伐替尼在HCC中的抗肿瘤作用。我们的结果还表明，乐伐替尼和桦木醇联合治疗可协同抑制 HCC 细胞的增殖和克隆形成。桦木醇处理后的肝癌细胞中IL-1β的mRNA和蛋白表达显着降低，而肝癌细胞对乐伐替尼的敏感性增强。此外，我们发现IL-1β的敲低也增强了乐伐替尼的功效，重组IL-1β蛋白可以挽救肝细胞癌细胞中乐伐替尼降低的细胞活力。进一步的机制研究表明，桦木醇通过抑制 mTOR 信号通路来降低 HCC 细胞中 IL-1β 的水平。最后，接受联合治疗的异种移植小鼠模型中的肿瘤生长被显着抑制。总之，我们的研究表明，SREBP2 抑制剂桦木醇通过抑制 mTOR/IL-1β 通路使肝细胞癌对乐伐替尼敏感，这可能是 HCC 患者的一种有前景的治疗策略。
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 element-binding 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-1β are 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-1β also enhances the efficacy of lenvatinib, and recombinant IL-1β protein rescues cell viability, which is reduced by lenvatinib in HCC cells. Further mechanistic studies indicate that betulin decreases the level of IL-1β in 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-1β pathway, which may be a promising therapeutic strategy for patients with HCC.
登录
查看更多内容
影响因子：
4.6
作者：
Ungerleider N;Han C;Zhang J;Yao L;Wu T
通讯作者：
Wu T
影响因子：
29
作者：
Westerterp M;Gautier EL;Ganda A;Molusky MM;Wang W;Fotakis P;Wang N;Randolph GJ;D'Agati VD;Yvan-Charvet L;Tall AR
通讯作者：
Tall AR
影响因子：
4.8
作者：
Shao, Weiqing;Zhu, Wenwei;Chen, Jinhong
通讯作者：
Chen, Jinhong
抑制 SREBP 会增加非小细胞肺癌细胞对吉非替尼的敏感性。
影响因子：
--
作者：
Li J;Yan H;Zhao L;Jia W;Yang H;Liu L;Zhou X;Miao P;Sun X;Song S;Zhao X;Liu J;Huang G
通讯作者：
Huang G
影响因子：
11.2
作者：
Kuzu OF;Noory MA;Robertson GP
通讯作者：
Robertson GP