The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress.
The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress.
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DOI：
10.2174/1566524016666160523143937
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发表时间：
2016
影响因子：
2.5
通讯作者：
Majsterek I
中科院分区：
文献类型：
--
作者：
Rozpedek W;Pytel D;Mucha B;Leszczynska H;Diehl JA;Majsterek I
缺氧是肿瘤微环境的主要标志，与肿瘤的快速进展和转移的诱导密切相关。缺氧抑制二硫键的形成并损害内质网（ER）的蛋白质折叠。内质网应激通过诱导蛋白激酶rna样内质网激酶（PERK）激活未折叠蛋白反应（UPR）通路。结果，磷酸化的真核起始因子2α (eIF2α)水平显著升高，通过抑制全局蛋白合成和激活转录因子4 （ATF4）的选择性翻译，促进了促适应信号通路。相反，在长时间内质网应激的情况下，促适应反应失败，凋亡细胞死亡。有趣的是，与线粒体的活性类似，内质网也可能通过内质网应激介导的钙渗漏到细胞质中直接激活凋亡途径，从而导致死亡效应物的激活。ATF4-CHOP介导的几种促凋亡基因的诱导和抗凋亡Bcl-2蛋白合成的抑制也会导致凋亡细胞死亡。深入了解缺氧诱导内质网应激下肿瘤细胞从适应到凋亡的转变，可能为如何克服当前抗肿瘤治疗的局限性提供答案。靶向UPR通路的成分可能提供更有效的肿瘤细胞消除，从而有助于开发更有前途的抗肿瘤治疗剂。
Hypoxia is a major hallmark of the tumor microenvironment that is strictly associated with rapid cancer progression and induction of metastasis. Hypoxia inhibits disulfide bond formation and impairs protein folding in the Endoplasmic Reticulum (ER). The stress in the ER induces the activation of Unfolded Protein Response (UPR) pathways via the induction of protein kinase RNA-like endoplasmic reticulum kinase (PERK). As a result, the level of phosphorylated Eukaryotic Initiation Factor 2 alpha (eIF2α) is markedly elevated, resulting in the promotion of a pro-adaptive signaling pathway by the inhibition of global protein synthesis and selective translation of Activating Transcription Factor 4 (ATF4). On the contrary, during conditions of prolonged ER stress, pro-adaptive responses fail and apoptotic cell death ensues. Interestingly, similar to the activity of the mitochondria, the ER may also directly activate the apoptotic pathway through ER stress-mediated leakage of calcium into the cytoplasm that leads to the activation of death effectors. Apoptotic cell death also ensues by ATF4-CHOP- mediated induction of several pro-apoptotic genes and suppression of the synthesis of anti-apoptotic Bcl-2 proteins. Advancing molecular insight into the transition of tumor cells from adaptation to apoptosis under hypoxia-induced ER stress may provide answers on how to overcome the limitations of current anti-tumor therapies. Targeting components of the UPR pathways may provide more effective elimination of tumor cells and as a result, contribute to the development of more promising anti-tumor therapeutic agents.