Rozpedek W, Pytel D, Mucha B, Leszczynska H, Diehl J A, Majsterek I
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Hollings Cancer Center, HCC-709, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
Department of Clinical Chemistry and Biochemistry, Military-Medical Faculty, Medical University of Lodz, Hallera 1, 90-647 Lodz, Poland.
Curr Mol Med. 2016;16(6):533-44. doi: 10.2174/1566524016666160523143937.
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.
缺氧是肿瘤微环境的一个主要特征，与癌症的快速进展和转移的诱导密切相关。缺氧会抑制二硫键的形成，并损害内质网（ER）中的蛋白质折叠。内质网中的应激通过诱导蛋白激酶RNA样内质网激酶（PERK）来激活未折叠蛋白反应（UPR）途径。结果，真核起始因子2α（eIF2α）的磷酸化水平显著升高，通过抑制整体蛋白质合成和激活转录因子4（ATF4）的选择性翻译，促进了一种适应性信号通路。相反，在长期内质网应激的情况下，适应性反应失败，细胞凋亡随之发生。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泄漏到细胞质中直接激活凋亡途径，从而导致死亡效应器的激活。凋亡细胞死亡也通过ATF4-CHOP介导的几种促凋亡基因的诱导和抗凋亡Bcl-2蛋白合成的抑制而发生。深入了解缺氧诱导的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途径的成分可能会更有效地消除肿瘤细胞，从而有助于开发更有前景的抗肿瘤治疗药物。
