Simvastatin induces apoptosis in human breast cancer cells: p53 and estrogen receptor independent pathway requiring signalling through JNK
Simvastatin induces apoptosis in human breast cancer cells: p53 and estrogen receptor independent pathway requiring signalling through JNK
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DOI：
10.1016/j.canlet.2006.10.009
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发表时间：
2007-06-08
期刊：
影响因子：
9.7
通讯作者：
Altiok, Nedret
中科院分区：
文献类型：
--
作者：
Koyuturk, Meral;Ersoz, Melike;Altiok, Nedret
辛伐他汀是一种广泛用于治疗高胆固醇血症的他汀类药物，在雌激素受体 (ER) 阳性 MCF-7 和 ER 阴性 MDA-MB 231 人乳腺癌细胞系中研究了其效果。辛伐他汀诱导两种细胞的细胞周期停滞和细胞凋亡。 17-β-雌二醇治疗不会改变辛伐他汀的这些作用。MCF-7 细胞表达野生型肿瘤抑制蛋白 p53，而 MDA-MB 231 细胞携带 p53 突变。然而，在任一种细胞系中，辛伐他汀处理均未观察到 p53 水平或定位的改变。另一方面，辛伐他汀强烈刺激c-jun的磷酸化，而c-jun NH2末端激酶（JNK）抑制剂SP600125完全消除了c-jun的磷酸化，这也显着降低了辛伐他汀在这些细胞中的抗增殖和凋亡作用。 总之，我们在此描述辛伐他汀通过参与乳腺癌细胞中的JNK诱导细胞凋亡，而与乳腺癌细胞的ER或p53表达状态无关。这些发现表明他汀类药物在治疗对目前使用的药物耐药的癌症方面具有巨大潜力，并针对 JNK 信号通路作为乳腺癌治疗的新方法。 (c) 2006 Elsevier Ireland Ltd. 保留所有权利。
The effect of simvastatin, a widely used statin for the treatment of hypercholesterolemia, was investigated in the estrogen receptor (ER)-positive MCF-7, and the ER-negative MDA-MB 231 human breast cancer cell lines. Simvastatin induced cell cycle arrest and apoptosis in both cells. These effects of simvastatin were not altered by 17-beta-estradiol treatment.MCF-7 cells express wild-type tumor suppressor protein p53, whereas MDA-MB 231 cells carry a p53 mutation. However, no alteration in the level or localisation of p53 was observed with simvastatin treatment in either cell line. On the other hand, simvastatin strongly stimulated phosphorylation of c-jun which was completely abolished by the c-jun NH2-terminal kinase (JNK) inhibitor SP600125, which also significantly reduced the antiproliferative and apoptotic effects of simvastatin in these cells.In conclusion, we describe here that simvastatin induces apoptosis via involvement of JNK in breast cancer cells independent of their ER or p53 expression status. These findings indicate a great potential for statins for the treatment of cancers resistant to currently used drugs, and target the JNK signalling pathway for a novel approach of breast cancer treatment. (c) 2006 Elsevier Ireland Ltd. All rights reserved.