An oasis in the desert of cancer chemotherapeutic resistance: The enlightenment from reciprocal crosstalk between signaling pathways of UPR and autophagy in cancers
An oasis in the desert of cancer chemotherapeutic resistance: The enlightenment from reciprocal crosstalk between signaling pathways of UPR and autophagy in cancers
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癌症化疗耐药沙漠中的绿洲：癌症中UPR与自噬信号通路相互串扰的启示
DOI：
10.1016/j.biopha.2017.05.132
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发表时间：
2017
影响因子：
7.5
通讯作者：
Jiang Lingfan
中科院分区：
文献类型：
--
作者：
Zhang Yuhang;Qu Xianjun;Jiang Lingfan
内质网（ER），主要但复杂，作为多效性细胞器的功能，适当的蛋白质折叠，Ca 2+储存以及脂质和碳水化合物代谢。多种微环境损伤包括但不限于炎症反应、葡萄糖失衡和缺氧，引起潜在毒性的未折叠蛋白在ER腔中的积累。在这些细胞威胁的条件下，自噬可能会启动包含30多个自噬相关基因（ATGs）的精心策划的程序，以降解和回收累积的错误折叠蛋白和其他相关的异常细胞质成分。目前研究证实UPR与自噬之间的联系为PERK-eIF 2 α-ATF 4信号通路，ATF 4介导的转录因子C/EBP同源物（CHOP）对十几个ATG基因的转录调控也得到进一步证实。最近的研究表明，这些信号系统之间的串扰可能是许多癌症化疗耐药的主要原因，因为化疗耐药表型通常伴随着药物给药引发炎症微环境和其他稳态障碍时自噬增加。本文综述了UPR与自噬信号通路之间的分子联系，以及针对该通路的潜在抑制剂的研究进展。
Endoplasmic reticulum (ER), principal but complex, functions as the pleiotropic organelle for proper protein folding, Ca2+storage as well as lipid and carbohydrate metabolisms. Diverse microenviromental insults including, but not limited to, inflammatory reaction, glucose imbalance and hypoxia, elicit the accumulation of potentially toxic unfolded proteins in the ER lumen. Under the condition of these cellular threats, the autophagy with the well-orchestrated program containing over 30 autophagy-related genes (ATGs) might be initiated for degrading and recycling of the cumulative misfolded proteins and other related abnormal cytoplasmic components. The link between UPR and autophagy has been verified as the PERK-eIF2α-ATF4 signaling pathway by ongoing research, and the transcription factor C/EBP homologous (CHOP) mediated by ATF4 were further substantiated to regulate a dozen of ATG genes transcriptionally. Recent researches showed that the crosstalk between these signaling systems might mainly account for chemotherapy resistance in many cancers because the chemoresistant phenotypes are usually concomitant with increasing autophagy when drugs were administrated to trigger inflammatory microenvironment and other dyshomeostasis. We summarized recent researches in the molecular link between UPR and autophagy signaling pathways as well as the perspectives of potential inhibitors targeting the Achilles heel for further clinical use.