Xanthine oxidoreductase mediates genotoxic drug‐induced autophagy and apoptosis resistance by uric acid accumulation and TGF ‐β‐activated kinase 1 (TAK 1) activation
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Abstract Autophagy is a highly conserved cellular process that profoundly impacts the efficacy of genotoxic chemotherapeutic drugs. TGF‐β‐activated kinase 1 (TAK1) is a serine/threonine kinase that activates several signaling pathways involved in inducing autophagy and suppressing cell death. Xanthine oxidoreductase (XOR) is a rate‐limiting enzyme that converts hypoxanthine to xanthine, and xanthine to uric acid and hydrogen peroxide in the purine catabolism pathway. Recent studies showed that uric acid can bind to TAK1 and prolong its activation. We hypothesized that genotoxic drugs may induce autophagy and apoptosis resistance by activating TAK1 through XOR‐generated uric acid. Here, we report that gemcitabine and 5‐fluorouracil (5‐FU), two genotoxic drugs, induced autophagy in HeLa and HT‐29 cells by activating TAK1 and its two downstream kinases, AMP‐activated kinase (AMPK) and c‐Jun terminal kinase (JNK). XOR knockdown and the XOR inhibitor allopurinol blocked gemcitabine‐induced TAK1, JNK, AMPK, and Unc51‐like kinase 1 (ULK1) S555 phosphorylation and gemcitabine‐induced autophagy. Inhibition of the ATM‐Chk pathway, which inhibits genotoxic drug‐induced uric acid production, blocked gemcitabine‐induced autophagy by inhibiting TAK1 activation. Exogenous uric acid in its salt form, monosodium urate (MSU), induced autophagy by activating TAK1 and its downstream kinases JNK and AMPK. Gene knockdown or the inhibitors of these kinases blocked gemcitabine‐ and MSU‐induced autophagy. Inhibition of autophagy by allopurinol, chloroquine, and 5Z‐7‐oxozeaenol (5Z), a TAK1‐specific inhibitor, enhanced gemcitabine‐induced apoptosis. Our study uncovers a previously unrecognized role of XOR in regulating genotoxic drug‐induced autophagy and apoptosis and has implications for designing novel therapeutic strategies for cancer treatment.Inducer
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Autophagy is an evolutionarily conserved biological phenomenon related to protein degradation and organelle turnover. Three types of autophagy have been defined: macroautophagy, microautophagy, and chaperone-mediated autophagy, which differ the way of in the delivery of substrates to the lysosome. In macroautophagy, substrates are wrapped in a double membrane structure, called the autophagosome. The formation of the autophagosome and its fusion with the lysosome are genetically controlled by a series of autophagy molecules and are activated in response to a number of environmental cues. Much has yet to be learned about the signaling pathway and the molecular mechanisms about this process. Autophagy is important to multiple cellular functions, particularly for nutrient and energy balance, and the turnover of cellular substances. The relationship of autophagy with cell death is complicated and may be context-dependent. Whereas the nature of autophagic death has yet to be carefully defined, it seems that autophagy may, in fact, be a key regulator of both apoptosis and necrosis. In this context, the roles of macroautophagy in both prosurvival and prodeath have been identified. Understanding the circumstance in which autophagy affects cell functions and therefore cell viability is critical for the future intervention of this process to control cancer, tissue injury, and other disease processes.
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Bcl-2 family proteins are known to regulate mitochondrial integrity and apoptosis. More recently, they have been found to play a role in regulating autophagy. Autophagy is a process involved in removing excess or damaged organelles. Bnip3 is a pro-apoptotic BH3-only protein which is known to cause mitochondrial dysfunction and cell death. Bnip3 is also a potent inducer of mitochondrial autophagy. In this study I have investigated the mechanism by which Bnip3 promotes removal of mitochondria via autophagy. Bnip3 contains a C-terminal transmembrane (TM) domain that is essential for homodimerization and pro- apoptotic function. Here, I show that Bnip3 homodimerization is also a requirement for induction of autophagy. Mutations in Bnip3 that disrupt homodimerization, but do not interfere with mitochondrial localization, failed to induce autophagy. In addition, I found that endogenous Bnip3 was localized to both the mitochondria and the endoplasmic reticulum (ER) in HeLa cells. To investigate the effects of Bnip3 at ER on autophagy, Bnip3 was targeted specifically to mitochondria or ER by substituting the Bnip3 TM domain with that of Acta or cytochromeb5, respectively. Interestingly, Bnip3 induced significant autophagy in cells from both sites. Moreover, Bnip3 induced removal of mitochondria and ER by autophagy via binding to LC3 on the autophagosome. Ablation of the Bnip3-LC3 interaction had no effect on the induction of general autophagy but significantly reduced autophagy of mitochondria and ER. Thus, our data suggest that the Bnip3 homodimer functions as an autophagy receptor to ensure removal of mitochondria and ER
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macroautophagy 的角色(此后 autophagy ) 在癌症，到临床的干预的生物学和反应是复杂的。autophagy 是在许多肿瘤背景的 dysregulated，是清楚的，在肿瘤开始和前进期间，并且响应治疗。然而，在控制房间行为的 autophagy 的多种的机械学的角色使在一个给定的肿瘤背景预言困难 autophagy 的角色，并且，由扩展，指向 autophagy 的治疗学的结果，力量。在这评论，我们在在癌症支持 pro-tumorigenic 和 anti-tumorigenic 和 autophagy 的治疗学的角色的文学总结证据。这概述在滋养的管理，房间死亡，房间老朽， proteotoxic 应力的规定和细胞的动态平衡包含 autophagy 的角色，在在新陈代谢的变化的肿瘤主人相互作用和参予的规定。在可能的地方，我们也试着理解，为 autophagy 的这些角色的机械学的底。我们明确地阐述在在 vivo.We 使这些问题清楚些的癌症的模型也考虑 autophagy 蛋白质的任何东西或上述所有函数怎么可能是可指向的由的遗传上设计的老鼠的新兴的角色现存或 pharmacologic 代理人的未来类。我们由简短在细胞的过程为关键 autophagy 蛋白质的子集探索不在经典中的角色得出结论，并且这些怎么可能在癌症之上影响。
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Autophagy is an evolutionarily conserved cellular catabolic pathway in response to metabolic stresses.Autophagy is activated with the formation of double-membrane structures named autophagosome,which can ferry cytoplasmic impaired organelles and proteins to the lysosome for degradation.Autophagy is regarded as a quality control mechanism that contributes to the maintainance of cell homeostasis.By far,the core proteins involved in the classical autophagy pathway have been identified.The activity and function of these proteins in autophagy flux following stress signal inputs is being investigated.We reviewed recent studies about the regulation of autophagy-related proteins with posttranslational modifications under conditions of metabolic stresses,in order to help the further understanding of autophagy.
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Autophagy 是导致长寿蛋白质和不正常的细胞器的降级的高度调整的细胞的机制。这个过程处于与神经病学的疾病相关的许多生理、病理学的条件被含有。最近的研究证明在服的局部缺血的 autophagy 的存在，而是没有一致还处于这个条件关于 autophagy 的功能被到达了。这篇文章在服的局部缺血或灌注期间加亮 autophagy 的激活，特别在神经原和星形细胞，以及在 neuronal 或 astrocytic 房间死亡和幸存的 autophagy 的角色。我们建议那 autophagy 的生理的层次，大概引起了由对谦虚组织缺氧或局部缺血温和，看起来保护。然而，严重组织缺氧或局部缺血或灌注引起的 autophagy 的高水平可以引起自我消化和最终的 neuronal 和 astrocytic 房间死亡。我们也讨论那氧化并且 endoplasmic 蜂窝胃(嗯) 在服的组织缺氧或局部缺血或灌注的压力是在神经原和星形细胞的 autophagy 的有势力刺激。另外，我们考察一方面建议在 autophagy 之间的可观的重叠的证据，和 apoptosis，坏死和 necroptosis 在另一方面，在决定结果和损坏神经原和星形细胞的最后的形态学。
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