ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner.
ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner.
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DOI：
10.1038/onc.2017.146
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发表时间：
2017-10-05
期刊：
影响因子：
8
通讯作者：
Savaskan N
中科院分区：
文献类型：
--
作者：
Chen D;Fan Z;Rauh M;Buchfelder M;Eyupoglu IY;Savaskan N
转录激活因子4（ATF 4）是代谢和氧化稳态和细胞存活的关键介质。ATF 4在不同的微环境应激反应中升高，包括饥饿，ER应激损伤和暴露于毒性因子。在这里，我们表明，ATF 4的表达促进原发性脑肿瘤（WHO 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，ATF 4表达促进细胞迁移和锚定非依赖性细胞生长，而siRNA介导的ATF 4敲低减弱了人类胶质瘤中恶性肿瘤的这些特征。进一步的实验表明，ATF 4依赖性肿瘤促进作用是由转录靶向谷氨酸反向转运体xCT/SCL 7A 11（也称为系统XC-）介导的。因此，由于ATF 4激活，xCT升高。我们进一步发现证据表明，ATF 4诱导的增殖可以通过药理学或遗传学xCT抑制和铁凋亡诱导剂如索拉非尼、erastin和GPx 4抑制剂RSL 3来减弱。此外，培育的xCT表达促进ATF 4敲减细胞中的细胞存活和生长。此外，增加xCT水平改善索拉非尼和erastin诱导的铁凋亡。相反，ATF 4敲低使细胞对erastin、索拉非尼和RSL 3诱导的铁凋亡易感。我们进一步鉴定了ATF 4促进肿瘤介导的神经元细胞死亡，这可以通过xCT抑制来减轻。此外，神经胶质瘤中升高的ATF 4表达促进肿瘤血管生成。值得注意的是，ATF 4诱导的血管生成可以通过铁凋亡诱导剂erastin和GPx 4抑制剂RSL 3减少。我们的数据提供了原理证明的证据，即ATF 4促进增殖并诱导有毒的微环境生态位。此外，ATF 4增加肿瘤血管生成并以xCT依赖性方式塑造血管结构。因此，抑制ATF 4是通过使肿瘤细胞对铁凋亡敏感来减少肿瘤生长和脉管系统的有效靶标。
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.
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影响因子：
--
作者：
Ghoochani A;Yakubov E;Sehm T;Fan Z;Hock S;Buchfelder M;Eyüpoglu IY;Savaskan NE
通讯作者：
Savaskan NE
影响因子：
21.3
作者：
通讯作者：
--
DOI：
10.1161/atvbaha.115.307087
发表时间：
2016-04
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Castranova D;Davis AE;Lo BD;Miller MF;Paukstelis PJ;Swift MR;Pham VN;Torres-Vázquez J;Bell K;Shaw KM;Kamei M;Weinstein BM
通讯作者：
Weinstein BM
影响因子：
8
作者：
Ghoochani, A.;Schwarz, M. A.;Eyupoglu, I. Y.
通讯作者：
Eyupoglu, I. Y.
影响因子：
16
作者：
Harding, HP;Novoa, I;Ron, D
通讯作者：
Ron, D