Mitochondrial superoxide mediates doxorubicin-induced keratinocyte apoptosis through oxidative modification of ERK and Bcl-2 ubiquitination.
Mitochondrial superoxide mediates doxorubicin-induced keratinocyte apoptosis through oxidative modification of ERK and Bcl-2 ubiquitination.
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DOI：
10.1016/j.bcp.2012.03.010
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发表时间：
2012-06-15
影响因子：
5.8
通讯作者：
Rojanasakul, Yon
中科院分区：
文献类型：
--
作者：
Luanpitpong, Sudjit;Chanvorachote, Pithi;Nimmannit, Ubonthip;Leonard, Stephen S.;Stehlik, Christian;Wang, Liying;Rojanasakul, Yon
角质形成细胞的大量凋亡与化疗引起的皮肤毒性的发病机制有关，但其潜在的作用机制尚不清楚。本研究调查了阿霉素 (DOX) 对 HaCaT 角质形成细胞的凋亡作用并确定了其潜在机制。用 DOX 处理细胞会诱导活性氧 (ROS) 产生，并通过不依赖于 p53 的线粒体死亡途径伴随凋亡细胞死亡的增加。电子自旋共振和流式细胞术研究表明，超氧化物是 DOX 诱导的主要氧化物质，负责死亡诱导作用。线粒体超氧化物清除酶 (MnSOD) 的异位表达或用 MnSOD 模拟物 (MnTBAP) 处理可抑制 DOX 诱导的超氧化物生成和细胞凋亡。超氧化物介导 DOX 凋亡作用的机制被证明涉及通过泛素蛋白酶体降解下调 Bcl-2。超氧化物通过 MAP 激酶 ERK1/2 失活诱导 Bcl-2 去磷酸化，从而促进 Bcl-2 泛素化。我们还提供了通过半胱氨酸磺酸形成对 ERK1/2 进行氧化修饰的证据。这些发现表明了凋亡调节蛋白氧化还原调节的新途径，这对于理解化疗引起的毒性和开发目前缺乏的预防性治疗策略可能很重要。
Massive apoptosis of keratinocytes has been implicated in the pathogenesis of chemotherapy-induced skin toxicities, but the underlying mechanisms of action are not well understood. The present study investigated the apoptotic effect of doxorubicin (DOX) on HaCaT keratinocytes and determined the underlying mechanisms. Treatment of the cells with DOX induced reactive oxygen species (ROS) generation and a concomitant increase in apoptotic cell death through the mitochondrial death pathway independent of p53. Electron spin resonance and flow cytometry studies showed that superoxide is the primary oxidative species induced by DOX and responsible for the death inducing effect. Ectopic expression of mitochondrial superoxide scavenging enzyme (MnSOD) or treatment with MnSOD mimetic (MnTBAP) inhibited DOX-induced superoxide generation and apoptosis. The mechanism by which superoxide mediates the apoptotic effect of DOX was shown to involve downregulation of Bcl-2 through ubiquitin-proteasomal degradation. Superoxide induces dephosphorylation of Bcl-2 through MAP kinase ERK1/2 inactivation which promotes ubiquitination of Bcl-2. We also provide evidence for the oxidative modification of ERK1/2 through cysteine sulfenic acid formation. These findings indicate a novel pathway for redox regulation of apoptosis regulatory proteins which could be important in the understanding of chemotherapy-induced toxicities and development of preventive treatment strategies which are currently lacking.
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