Nilotinib induces apoptosis and autophagic cell death of activated hepatic stellate cells via inhibition of histone deacetylases.
Nilotinib induces apoptosis and autophagic cell death of activated hepatic stellate cells via inhibition of histone deacetylases.
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DOI：
10.1016/j.bbamcr.2013.02.033
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发表时间：
2013-08
期刊：
影响因子：
--
通讯作者：
Mehal WZ
中科院分区：
文献类型：
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作者：
Shaker ME;Ghani A;Shiha GE;Ibrahim TM;Mehal WZ
增加肝星状细胞(HSC)的死亡是一种非常有吸引力的限制肝纤维化的方法。酪氨酸激酶抑制剂已被证明具有抗纤维化的特性，但其机制尚不清楚。在这里，我们确定了第二代酪氨酸激酶抑制剂尼洛替尼诱导HSC死亡的作用机制。用尼洛替尼及其前身伊马替尼在没有或存在各种已知干扰死亡信号通路的阻滞剂的情况下，处理人HSC株(LX-2)和大鼠HSC。尼洛替尼，而不是伊马替尼，以剂量依赖的方式诱导激活的但不是静止的HSC进行性死亡。激活的HSCs通过凋亡和自噬死亡，表现为DNA片段化和caspase激活增加，自噬标记、轻链(LC)3A-II和LC3B-II积聚。尽管用Z-VAD-FMK抑制caspase可抑制尼洛替尼诱导的HSCs的凋亡，但由于自噬加剧，HSCs的存活率并未增加。然而，用环孢菌素A阻断线粒体通透性转换孔(MPTP)的开放，可完全消除尼洛替尼引起的细胞凋亡和自噬。此外，尼洛替尼可降低组蛋白脱乙酰酶1、2和4的蛋白表达。有趣的是，选择性p300/CBP组蛋白乙酰转移酶抑制剂C646可使尼洛替尼诱导的细胞凋亡和自噬转向坏死。综上所述，MPTP是尼洛替尼在活化的HSC中的靶标，提示它与组蛋白脱乙酰酶的抑制作用相协调，从而诱导细胞凋亡和自噬。因此，我们的研究为尼洛替尼的抗纤维化作用提供了新的见解。
Increasing hepatic stellate cell (HSC) death is a very attractive approach for limiting liver fibrosis. Tyrosine kinase inhibitors have been shown to have anti-fibrotic properties, but the mechanisms are poorly understood. Here, we identified the mechanism of action of the second-generation tyrosine kinase inhibitor nilotinib in inducing HSC death. Human HSC line (LX-2) and rat HSCs were treated with nilotinib and its predecessor, imatinib, in the absence or presence of various blockers, known to interfere with death signaling pathways. Nilotinib, but not imatinib, induced progressive cell death of activated, but not quiescent, HSCs in a dose-dependent manner. Activated HSCs died through apoptosis, as denoted by increased DNA fragmentation and caspase activation, and through autophagy, as indicated by the accumulation of autophagic markers, light chain (LC)3A-II and LC3B-II. Although inhibition of caspases with Z-VAD-FMK suppressed nilotinib-induced HSCs apoptosis, there was no increase in HSCs survival, because autophagy was exacerbated. However, blocking the mitochondrial permeability transition pore (mPTP) opening with cyclosporin A completely abolished both apoptosis and autophagy due to nilotinib. Moreover, nilotinib treatment decreased the protein expression of histone deacetylases 1, 2 and 4. Interestingly, pretreament with C646, a selective p300/CBP histone acetyl transferase inhibitor, resulted in diverting nilotinib-induced apoptosis and autophagy towards necrosis. In conclusion, the identification of mPTP as a target of nilotinib in activated HSCs suggests a coordination with histone deacetylases inhibition to induce apoptosis and autophagy. Thus, our study provides novel insights into the anti-fibrotic effects of nilotinib.