Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Autophagy. 2013 Apr;9(4):612-4. doi: 10.4161/auto.23486. Epub 2013 Jan 17.
Stress in the tumor microenvironment in the form of hypoxia and low glucose/amino acid levels activates the evolutionarily conserved cellular adaptation program called the unfolded protein response (UPR) promoting cell survival in such conditions. Our recent studies showed that cell autonomous stress such as activation of the proto-oncogene MYC/c-Myc, can also trigger the UPR and induce endoplasmic reticulum (ER) stress-mediated autophagy. Amelioration of ER stress or autophagy enhances cancer cell death in vitro and attenuates tumor growth in vivo. Here we will discuss the role of the UPR and autophagy in MYC-induced transformation. Our findings demonstrate that the EIF2AK3/PERK-EIF2S1/eIF2α-ATF4 arm of the UPR promotes tumorigenesis by activating autophagy and enhancing tumor formation. Therefore, the UPR is an attractive target in MYC-driven cancers.
肿瘤微环境中的应激形式，如缺氧和低糖/氨基酸水平，会激活进化上保守的细胞适应程序，称为未折叠蛋白反应（UPR），从而促进细胞在这些条件下的存活。我们最近的研究表明，细胞自主应激，如原癌基因 MYC/c-Myc 的激活，也可以触发 UPR 并诱导内质网（ER）应激介导的自噬。减轻 ER 应激或自噬可增强体外癌细胞死亡，并减弱体内肿瘤生长。在这里，我们将讨论 UPR 和自噬在 MYC 诱导的转化中的作用。我们的研究结果表明，UPR 的 EIF2AK3/PERK-EIF2S1/eIF2α-ATF4 臂通过激活自噬和增强肿瘤形成来促进肿瘤发生。因此，UPR 是 MYC 驱动的癌症的一个有吸引力的靶点。
