Betulinic acid induces a novel cell death pathway that depends on cardiolipin modification
Betulinic acid induces a novel cell death pathway that depends on cardiolipin modification
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DOI：
10.1038/onc.2015.102
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发表时间：
2016-01-28
期刊：
影响因子：
8
通讯作者：
Medema, J. P.
中科院分区：
文献类型：
--
作者：
Potze, L.;Di Franco, S.;Medema, J. P.
癌症与脂质代谢的强烈变化有关。例如，正常细胞从循环中摄取脂肪酸（FA），而肿瘤细胞产生自己的并依赖于从头FA合成，这可能会使靶肿瘤细胞变得脆弱。桦木酸（BetA）是一种天然化合物，其通过不明确的机制选择性地杀死肿瘤细胞，该机制独立于BAX和巴克，但依赖于线粒体渗透性转换-孔开放。在这里，我们解开这一途径，并表明，BetA抑制的活性，甾醇-CoA-去饱和酶（SCD-1）。这种酶在肿瘤细胞中过表达，并且对于利用从头FA合成的细胞至关重要，因为它将新合成的饱和FA转化为不饱和FA。有趣的是，我们发现通过BetA或替代地用特异性SCD-1抑制剂抑制SCD-1直接且快速地影响心磷脂（CL）的饱和水平，心磷脂（CL）是一种具有重要结构和代谢功能的线粒体脂质，并且同时调节线粒体依赖性细胞死亡。由于增强的CL饱和，癌细胞的线粒体，而不是不依赖于从头FA合成的正常细胞，经历超微结构变化，释放细胞色素c并迅速诱导细胞死亡。重要的是，添加不饱和脂肪酸规避了SCD-1活性的需要，从而防止了BetA诱导的CL饱和和随后的细胞毒性，支持了这种新途径在BetA诱导的细胞毒性中的重要性。
Cancer is associated with strong changes in lipid metabolism. For instance, normal cells take up fatty acids (FAs) from the circulation, while tumour cells generate their own and become dependent on de novo FA synthesis, which could provide a vulnerability to target tumour cells. Betulinic acid (BetA) is a natural compound that selectively kills tumour cells through an ill-defined mechanism that is independent of BAX and BAK, but depends on mitochondrial permeability transition-pore opening. Here we unravel this pathway and show that BetA inhibits the activity of steroyl-CoA-desaturase (SCD-1). This enzyme is overexpressed in tumour cells and critically important for cells that utilize de novo FA synthesis as it converts newly synthesized saturated FAs to unsaturated FAs. Intriguingly, we find that inhibition of SCD-1 by BetA or, alternatively, with a specific SCD-1 inhibitor directly and rapidly impacts on the saturation level of cardiolipin (CL), a mitochondrial lipid that has important structural and metabolic functions and at the same time regulates mitochondria-dependent cell death. As a result of the enhanced CL saturation mitochondria of cancer cells, but not normal cells that do not depend on de novo FA synthesis, undergo ultrastructural changes, release cytochrome c and quickly induce cell death. Importantly, addition of unsaturated FAs circumvented the need for SCD-1 activity and thereby prevented BetA-induced CL saturation and subsequent cytotoxicity, supporting the importance of this novel pathway in the cytotoxicity induced by BetA.