Chen D, Fan Z, Rauh M, Buchfelder M, Eyupoglu I Y, Savaskan N
Translational Cell Biology &Neurooncology Laboratory, Universitätsklinikum Erlangen (UKER), Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
Department of Otolaryngology- Head and Neck Surgery, Chinese PLA General Hospital, Beijing, China.
Oncogene. 2017 Oct 5;36(40):5593-5608. doi: 10.1038/onc.2017.146. Epub 2017 May 29.
Activating transcription factor 4 (ATF4) is a critical mediator of metabolic and oxidative homeostasis and cell survival. ATF4 is elevated in response to diverse microenvironmental stresses, including starvation, ER stress damages and exposure to toxic factors. Here we show that ATF4 expression fosters the malignancy of primary brain tumors (WHO grade III and IV gliomas) and increases proliferation and tumor angiogenesis. Hence, ATF4 expression promotes cell migration and anchorage-independent cell growth, whereas siRNA-mediated knockdown of ATF4 attenuates these features of malignancy in human gliomas. Further experiments revealed that ATF4-dependent tumor promoting effects are mediated by transcriptional targeting the glutamate antiporter xCT/SCL7A11 (also known as system Xc). Thus, xCT is elevated as a consequence of ATF4 activation. We further found evidence that ATF4-induced proliferation can be attenuated by pharmacological or genetic xCT inhibition and ferroptosis inducers such as sorafenib, erastin and GPx4 inhibitor RSL3. Further, fostered xCT expression promotes cell survival and growth in ATF4 knockdown cells. Moreover, increased xCT levels ameliorate sorafenib and erastin-induced ferroptosis. Conversely, ATF4 knockdown renders cells susceptible for erastin, sorafenib and RSL3-induced ferroptosis. We further identified that ATF4 promotes tumor-mediated neuronal cell death which can be alleviated by xCT inhibition. Moreover, elevated ATF4 expression in gliomas promotes tumor angiogenesis. Noteworthy, ATF4-induced angiogenesis could be diminished by ferroptosis inducers erastin and by GPx4 inhibitor RSL3. Our data provide proof-of-principle evidence that ATF4 fosters proliferation and induces a toxic microenvironmental niche. Furthermore, ATF4 increases tumor angiogenesis and shapes the vascular architecture in a xCT-dependent manner. Thus, inhibition of ATF4 is a valid target for diminishing tumor growth and vasculature via sensitizing tumor cells for ferroptosis.
激活转录因子4（ATF4）是代谢和氧化稳态以及细胞存活的关键调节因子。ATF4会因多种微环境应激而升高，包括饥饿、内质网应激损伤和接触有毒因子。在此我们表明，ATF4的表达促进原发性脑肿瘤（世界卫生组织III级和IV级胶质瘤）的恶性程度，并增加增殖和肿瘤血管生成。因此，ATF4的表达促进细胞迁移和非锚定依赖性细胞生长，而siRNA介导的ATF4敲低会减弱人胶质瘤的这些恶性特征。进一步的实验表明，ATF4依赖的肿瘤促进作用是通过转录靶向谷氨酸反向转运体xCT/SCL7A11（也称为系统Xc）介导的。因此，xCT因ATF4的激活而升高。我们进一步发现证据表明，ATF4诱导的增殖可通过药理学或基因抑制xCT以及铁死亡诱导剂（如索拉非尼、艾拉司丁和谷胱甘肽过氧化物酶4抑制剂RSL3）而减弱。此外，增强的xCT表达促进ATF4敲低细胞的存活和生长。而且，升高的xCT水平可改善索拉非尼和艾拉司丁诱导的铁死亡。相反，ATF4敲低使细胞对艾拉司丁、索拉非尼和RSL3诱导的铁死亡敏感。我们进一步确定，ATF4促进肿瘤介导的神经元细胞死亡，而这种死亡可通过抑制xCT来缓解。此外，胶质瘤中升高的ATF4表达促进肿瘤血管生成。值得注意的是，ATF4诱导的血管生成可被铁死亡诱导剂艾拉司丁和谷胱甘肽过氧化物酶4抑制剂RSL3所减弱。我们的数据提供了原理性证据，表明ATF4促进增殖并诱导有毒的微环境生态位。此外，ATF4增加肿瘤血管生成并以xCT依赖的方式塑造血管结构。因此，抑制ATF4是通过使肿瘤细胞对铁死亡敏感来减少肿瘤生长和脉管系统的有效靶点。
