The Oxidation States of DJ-1 Dictate the Cell Fate in Response to Oxidative Stress Triggered by 4-HPR: Autophagy or Apoptosis?
The Oxidation States of DJ-1 Dictate the Cell Fate in Response to Oxidative Stress Triggered by 4-HPR: Autophagy or Apoptosis?
复制标题
DOI：
10.1089/ars.2013.5446
复制
发表时间：
2014-10-01
影响因子：
6.6
通讯作者：
Yang, Bo
中科院分区：
文献类型：
--
作者：
Cao, Ji;Ying, Meidan;Yang, Bo
目的：化疗诱导的活性氧（ROS）不仅参与细胞凋亡，而且还能引发自噬。由于自噬被报道可以保护癌细胞免于凋亡，这削弱了化疗的治疗效果。本研究旨在确定决定细胞对ROS反应的关键分子，从而提供更好的策略来提高化疗效率。结果如下：增加浓度的N-（4-羟基苯基）维甲酰胺（4-HPR）处理以剂量依赖性方式将自噬向下推至凋亡，并且4-HPR诱导的ROS有助于该过程。由于我们发现ASK 1调节的JNK 1和p38分别负责4-HPR诱导的自噬和凋亡，我们进一步利用免疫共沉淀，然后进行液相色谱-串联质谱分析，以确定在不同氧化状态下特异性结合ASK 1的蛋白质。值得注意的是，DJ-1是一种重要的抗氧化蛋白。有趣的是，DJ-1作为一种氧化还原传感器，可以感知ROS水平并决定细胞对4-HPR的反应：在轻度氧化应激下，DJ-1的中度氧化被招募来抑制ASK 1的活性并通过激活自噬来维持细胞活力;在致死水平的氧化应激下，过量氧化的DJ-1与ASK 1解离并激活它，从而启动p38活化并使细胞致力于凋亡。此外，DJ-1的缺失增加了肿瘤细胞在体外和体内对4-HPR的敏感性。创新：我们的研究结果表明，DJ-1的不同氧化态的功能作为细胞的氧化还原传感器的ROS引起的4-HPR和决定细胞的命运的自噬或凋亡。此外，结果表明DJ-1可能是癌症治疗的有效治疗靶点。结论：ROS介导的DJ-1氧化态的改变参与了4-HPR将自噬推向凋亡的作用。因此，这种变化通过调节DJ-1-ASK 1复合物的形成来介导ASK 1活化，并决定自噬或凋亡的细胞命运。
Aim: Chemotherapy-induced reactive oxygen species (ROS) not only contribute to apoptosis, but also trigger autophagy. Since autophagy is reported to protect cancer cells from apoptosis, this weakens the therapeutic effect of chemotherapy. This study aimed at identifying the key molecules that determine the cellular response to ROS and, therefore, provide better strategies to increase chemotherapeutic efficiency. Results: Increasing concentrations of N-(4-hydroxyphenyl) retinamide (4-HPR)-treatment pushed autophagy down to apoptosis in a dose-dependent manner, and 4-HPR-induced ROS contribute to this process. Since we found that ASK1-regulated JNK1 and p38 are responsible for 4-HPR-induced autophagy and apoptosis, respectively, we further utilized co-immunoprecipitation followed by liquid chromatography-tandem mass spectrometry analysis to identify proteins that specifically bind to ASK1 under different oxidative states. Of note, DJ-1, a crucial antioxidant protein, was identified. Interestingly, DJ-1 functions as a redox sensor that senses ROS levels and determines the cellular response to 4-HPR: Under mild oxidative stress, moderate oxidation of DJ-1 is recruited to inhibit the activity of ASK1 and maintain cell viability by activating autophagy; under a lethal level of oxidative stress, excessive oxidized DJ-1 dissociates from ASK1 and activates it, thereby initiating p38 activation and enabling the cells to commit to apoptosis. Moreover, the depletion of DJ-1 increases the sensitivity of tumor cells to 4-HPR both in vitro and in vivo. Innovation: Our results reveal that the different oxidation states of DJ-1 function as a cellular redox sensor of ROS caused by 4-HPR and determine the cell fate of autophagy or apoptosis. Moreover, the results suggest that DJ-1 might be a potent therapeutic target for cancer treatment. Conclusion: ROS-mediated changes in the oxidation state of DJ-1 are involved in 4-HPR's effect on pushing autophagy down to apoptosis. Consequently, this change mediates ASK1 activation by regulating DJ-1-ASK1 complex formation and determines the cell fate of autophagy or apoptosis.