Pagliarini Vittoria, Giglio Paola, Bernardoni Paolo, De Zio Daniela, Fimia Gian Maria, Piacentini Mauro, Corazzari Marco
National Institute for Infectious Disease 'L. Spallanzani' IRCCS, 00149 Rome, Italy.
Department of Biology, Unit of the Dulbecco Telethon Institute, University of Rome 'Tor Vergata', 00133 Rome, Italy Cell Stress and Survival Unit, Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen DK-2100, Denmark.
J Cell Sci. 2015 Mar 15;128(6):1166-79. doi: 10.1242/jcs.164103. Epub 2015 Jan 22.
The endoplasmic reticulum (ER) has recently emerged as an alternative target to induce cell death in tumours, because prolonged ER stress results in the induction of apoptosis even in chemoresistant transformed cells. Here, we show that the DNA-damage-responsive pro-apoptotic factor E2F1 is unexpectedly downregulated during the ER stress-mediated apoptotic programme. E2F1 decline is a late event during the ER response and is mediated by the two unfolded protein response (UPR) sensors ATF6 and IRE1 (also known as ERN1). Whereas ATF6 directly interacts with the E2F1 promoter, IRE1 requires the involvement of the known E2F1 modulator E2F7, through the activation of its main target Xbp-1. Importantly, inhibition of the E2F1 decrease prevents ER-stress-induced apoptosis, whereas E2F1 knockdown efficiently sensitises cells to ER stress-dependent apoptosis, leading to the upregulation of two main factors in the UPR pro-apoptotic execution phase, Puma and Noxa (also known as BBC3 and PMAIP1, respectively). Our results point to a novel key role of E2F1 in the cell survival/death decision under ER stress, and unveil E2F1 inactivation as a valuable novel potential therapeutic strategy to increase the response of tumour cells to ER stress-based anticancer treatments.
内质网（ER）最近已成为诱导肿瘤细胞死亡的另一个靶点，因为内质网应激延长即使在化疗耐药的转化细胞中也会诱导细胞凋亡。在此，我们表明，在应激介导的凋亡程序中，DNA损伤反应性促凋亡因子E2F1意外下调。E2F1的下降是内质网反应中的一个晚期事件，由两个未折叠蛋白反应（UPR）传感器ATF6和IRE1（也称为ERN1）介导。虽然ATF6直接与E2F1启动子相互作用，但IRE1需要已知的E2F1调节剂E2F7通过激活其主要靶点Xbp-1参与。重要的是，抑制E2F1的减少可防止内质网应激诱导的细胞凋亡，而敲低E2F1可有效使细胞对内质网应激依赖性凋亡敏感，导致未折叠蛋白反应促凋亡执行阶段的两个主要因子Puma和Noxa（也分别称为BBC3和PMAIP1）上调。我们的结果表明E2F1在内质网应激下的细胞存活/死亡决定中具有新的关键作用，并揭示E2F1失活是一种有价值的新型潜在治疗策略，可增强肿瘤细胞对内质网应激抗癌治疗的反应。
