Maprotiline Suppresses Cholesterol Biosynthesis and Hepatocellular Carcinoma Progression Through Direct Targeting of CRABP1.
Maprotiline Suppresses Cholesterol Biosynthesis and Hepatocellular Carcinoma Progression Through Direct Targeting of CRABP1.
复制标题
马普替林通过直接靶向 CRABP1 抑制胆固醇生物合成和肝细胞癌进展
DOI：
10.3389/fphar.2021.689767
复制
发表时间：
2021
影响因子：
5.6
通讯作者：
Xu W
中科院分区：
文献类型：
--
作者：
Zheng C;Zhu Y;Liu Q;Luo T;Xu W
肝细胞癌仍然是世界范围内与癌症相关的死亡的主要原因之一，预后不良，因此迫切需要更有效的药物。本文利用由FDA批准的1,056种药物组成的小分子药物文库来筛选抗癌药物。四环化合物麦普替林是一种高度选择性的去甲肾上腺素再摄取阻滞剂，具有很强的抗抑郁效果。然而，马普替林的抗癌作用尚不清楚。在这里，我们研究了马普替林在肝癌细胞株Huh7和HepG2中的抗癌作用。我们发现，麦普替林在体外不仅能显著抑制细胞增殖、克隆形成和转移，而且在体内也有抗肿瘤作用。除单独的抗肿瘤作用外，马普替林还可增强肝癌细胞对索拉非尼的敏感性。深入研究表明，麦普替林通过ERK信号通路显著降低固醇调节元件结合蛋白2(SREBP2)的磷酸化，从而导致胆固醇生物合成减少，最终阻碍肝癌细胞的生长。此外，我们还发现细胞维甲酸结合蛋白1(CRABP1)是马普替林的直接靶点。综上所述，本研究首次发现马普替林通过直接与CRABP1结合，通过ERK-SREBP2信号通路抑制胆固醇的生物合成，从而抑制肝癌细胞的增殖和转移，这支持了马普替林在肝癌治疗中的再利用策略。
Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related death and has a poor prognosis worldwide, thus, more effective drugs are urgently needed. In this article, a small molecule drug library composed of 1,056 approved medicines from the FDA was used to screen for anticancer drugs. The tetracyclic compound maprotiline, a highly selective noradrenergic reuptake blocker, has strong antidepressant efficacy. However, the anticancer effect of maprotiline remains unclear. Here, we investigated the anticancer potential of maprotiline in the HCC cell lines Huh7 and HepG2. We found that maprotiline not only significantly restrained cell proliferation, colony formation and metastasis in vitro but also exerted antitumor effects in vivo. In addition to the antitumor effect alone, maprotiline could also enhance the sensitivity of HCC cells to sorafenib. The depth studies revealed that maprotiline substantially decreased the phosphorylation of sterol regulatory element-binding protein 2 (SREBP2) through the ERK signaling pathway, which resulted in decreased cholesterol biosynthesis and eventually impeded HCC cell growth. Furthermore, we identified cellular retinoic acid binding protein 1 (CRABP1) as a direct target of maprotiline. In conclusion, our study provided the first evidence showing that maprotiline could attenuate cholesterol biosynthesis to inhibit the proliferation and metastasis of HCC cells through the ERK-SREBP2 signaling pathway by directly binding to CRABP1, which supports the strategy of repurposing maprotiline in the treatment of HCC.
登录
查看更多内容
外泌体 microRNA-32-5p 通过 PI3K/Akt 途径诱导肝细胞癌多药耐药
DOI：
10.1186/s13046-018-0677-7
发表时间：
2018-03-12
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Fu X;Liu M;Qu S;Ma J;Zhang Y;Shi T;Wen H;Yang Y;Wang S;Wang J;Nan K;Yao Y;Tian T
通讯作者：
Tian T
CD24通过激活肝细胞癌自噬调节索拉非尼耐药
影响因子：
9
作者：
Lu S;Yao Y;Xu G;Zhou C;Zhang Y;Sun J;Jiang R;Shao Q;Chen Y
通讯作者：
Chen Y
抗过敏药物氮卓斯汀通过直接靶向ARF1抑制IQGAP1-ERK-Drp1介导的线粒体裂变抑制结肠肿瘤发生
影响因子：
12.4
作者：
Hu HF;Xu WW;Li YJ;He Y;Zhang WX;Liao L;Zhang QH;Han L;Yin XF;Zhao XX;Pan YL;Li B;He QY
通讯作者：
He QY
影响因子：
4.6
作者：
Persaud SD;Park SW;Ishigami-Yuasa M;Koyano-Nakagawa N;Kagechika H;Wei LN
通讯作者：
Wei LN
影响因子：
5
作者：
Ferrer-Villada, T;Navarro-Polanco, RA;Sánchez-Chapula, JA
通讯作者：
Sánchez-Chapula, JA