Sorafenib kills liver cancer cells by disrupting SCD1-mediated synthesis of monounsaturated fatty acids via the ATP-AMPK-mTOR-SREBP1 signaling pathway
Sorafenib kills liver cancer cells by disrupting SCD1-mediated synthesis of monounsaturated fatty acids via the ATP-AMPK-mTOR-SREBP1 signaling pathway
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DOI：
10.1096/fj.201802619rr
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发表时间：
2019-09-01
期刊：
影响因子：
4.8
通讯作者：
Sun, Chaomin
中科院分区：
文献类型：
--
作者：
Liu, Ge;Kuang, Shan;Sun, Chaomin
索拉非尼是一种多激酶抑制剂，可有效治疗晚期肝癌。尽管索拉非尼通过几种已建立的癌症相关蛋白激酶靶点的作用机制已得到充分表征，但索拉非尼在人类肿瘤中诱导不同的反应，而这种变化的原因尚不清楚。为了研究潜在的机制，我们将基于质谱的蛋白质组学分析应用于Huh 7.5人肝癌细胞，发现索拉非尼显著影响这些细胞中关键脂肪生成酶的表达，特别是硬脂酰辅酶A去饱和酶1（SCD 1）。鉴于SCD 1催化单不饱和脂肪酸（FA）合成中最关键和限速的步骤，我们进行了脂质组学分析，结果显示索拉非尼处理的细胞中脂质谱发生了显著变化。游离脂肪酸的检测和分析表明，单不饱和脂肪酸的水平，包括油酸，在索拉非尼处理的那些细胞中显着降低。油酸的加入保护肝癌细胞免于索拉非尼诱导的死亡，并减轻药物引起的线粒体形态和功能异常。索拉非尼治疗抑制ATP产生，导致AMPK通过磷酸化活化。进一步的次要作用包括降低肝癌细胞中固醇调节元件结合蛋白1（SREBP1）的水平和雷帕霉素哺乳动物靶蛋白（mTOR）的磷酸化。这些作用在化合物C（AMPK抑制剂）和ATP和腺苷的存在下被部分消除，并且SREBP1c过表达也可以抵抗索拉非尼的作用，这表明索拉非尼诱导的细胞活力降低是由ATP-AMPK-mTOR-SREBP1信号通路介导的。总之，我们的研究结果表明，索拉非尼在肝癌细胞中的抗癌活性是基于抑制ATP的产生，SCD 1的表达，和单不饱和脂肪酸的合成。此外，单不饱和脂肪酸合成的减少进一步引发索拉非尼处理的细胞中ATP产生的更严重的减少。据我们所知，这是索拉非尼通过ATP-AMPK-mTOR-SREBP1通路靶向SCD 1破坏脂肪生成并引发肝癌细胞死亡的第一个证据。Liu，G.，匡，S.，曹河，俄-地王杰，Peng，Q.，孙角，澳-地索拉非尼通过ATP-AMPK-mTOR-SREBP1信号通路破坏SCD 1介导的单不饱和脂肪酸合成来杀死肝癌细胞。
Sorafenib is a multikinase inhibitor that is effective in treating advanced liver cancer. Although its mechanism of action through several established cancer-related protein kinase targets is well-characterized, sorafenib induces variable responses among human tumors, and the cause for this variation is yet unknown. To investigate the underlying mechanisms, we applied mass spectrometry-based proteomic analysis to Huh7.5 human liver cancer cells and found that sorafenib significantly affected the expression of the key lipogenic enzymes, especially stearoyl coenzyme A desaturase 1 (SCD1), in these cells. Given that SCD1 catalyzes the most crucial and rate-limiting step in the synthesis of monounsaturated fatty acids (FAs), we performed a lipidomic analysis, which showed a dramatically altered lipid profile in sorafenib-treated cells. Detection and analysis of free FAs showed that the levels of monounsaturated FAs, including oleate, were significantly decreased in those cells treated by sorafenib. Addition of oleate protected liver cancer cells from sorafenib-induced death and alleviated the abnormalities of mitochondrial morphology and function caused by the drug. Treatment with sorafenib suppressed ATP production, resulting in AMPK activation via phosphorylation. Further secondary effects included reduction of the levels of sterol regulatory element-binding protein 1 (SREBP1) and the phosphorylation of mammalian target of rapamycin (mTOR) in liver cancer cells. These effects were partly abolished in the presence of compound C (an AMPK inhibitor) and ATP and adenosine, and SREBP1c overexpression also could be resistant to the effects of sorafenib, suggesting that the sorafenib-induced reduction in cell viability was mediated by the ATP-AMPK-mTOR-SREBP1 signaling pathway. Taken together, our results suggest that sorafenib's anticancer activity in liver cancer cells is based on the inhibition of ATP production, SCD1 expression, and monounsaturated FA synthesis. In addition, the decreased monounsaturated FA synthesis further triggered the more serious reduction of ATP production in sorafenib-treated cells. To our knowledge, this is the first evidence that sorafenib disrupts lipogenesis and triggers liver cancer cell death by targeting SCD1 through the ATP-AMPK-mTOR-SREBP1 pathway.-Liu, G., Kuang, S., Cao, R., Wang, J., Peng, Q., Sun, C. Sorafenib kills liver cancer cells by disrupting SCD1-mediated synthesis of monounsaturated fatty acids via the ATP-AMPK-mTOR- SREBP1 signaling pathway.