Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, 90-419 Lodz, Poland.
Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
Int J Mol Sci. 2019 Sep 5;20(18):4354. doi: 10.3390/ijms20184354.
Cancer constitutes a grave problem nowadays in view of the fact that it has become one of the main causes of death worldwide. Poor clinical prognosis is presumably due to cancer cells metabolism as tumor microenvironment is affected by oxidative stress. This event triggers adequate cellular response and thereby creates appropriate conditions for further cancer progression. Endoplasmic reticulum (ER) stress occurs when the balance between an ability of the ER to fold and transfer proteins and the degradation of the misfolded ones become distorted. Since ER is an organelle relatively sensitive to oxidative damage, aforementioned conditions swiftly cause the activation of the unfolded protein response (UPR) signaling pathway. The output of the UPR, depending on numerous factors, may vary and switch between the pro-survival and the pro-apoptotic branch, and hence it displays opposing effects in deciding the fate of the cancer cell. The role of UPR-related proteins in tumorigenesis, such as binding the immunoglobulin protein (BiP) and inositol-requiring enzyme-1α (IRE1α), activating transcription factor 6 (ATF6) or the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), has already been specifically described so far. Nevertheless, due to the paradoxical outcomes of the UPR activation as well as gaps in current knowledge, it still needs to be further investigated. Herein we would like to elicit the actual link between neoplastic diseases and the UPR signaling pathway, considering its major branches and discussing its potential use in the development of a novel, anti-cancer, targeted therapy.
癌症是当今一个严重的问题，因为它已成为全球主要死亡原因之一。较差的临床预后可能是由于癌细胞代谢所致，因为肿瘤微环境受到氧化应激的影响。这一事件引发了适当的细胞反应，从而为癌症进一步发展创造了适当的条件。内质网（ER）应激发生在 ER 折叠和转移蛋白质的能力与错误折叠蛋白质的降解之间的平衡被扭曲时。由于 ER 是一个对氧化损伤相对敏感的细胞器，上述情况会迅速导致未折叠蛋白质反应（UPR）信号通路的激活。UPR 的输出取决于许多因素，可能在促生存和促凋亡分支之间变化和切换，因此在决定癌细胞命运方面表现出相反的效果。UPR 相关蛋白在肿瘤发生中的作用，如结合免疫球蛋白蛋白（BiP）和必需的肌醇酶 1α（IRE1α）、激活转录因子 6（ATF6）或蛋白激酶 R（PKR）样内质网激酶（PERK），迄今为止已经被具体描述。然而，由于 UPR 激活的矛盾结果以及当前知识的空白，它仍需要进一步研究。在此，我们将探讨肿瘤疾病与 UPR 信号通路之间的实际联系，考虑其主要分支，并讨论其在开发新型抗癌靶向治疗中的潜在用途。
