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dc.contributor.author
Chen, D.
dc.contributor.author
Fan, Z.
dc.contributor.author
Rauh, M.
dc.contributor.author
Buchfelder, Michael
dc.contributor.author
Eyupoglu, I. Y.
dc.contributor.author
Savaskan, N.
dc.date.accessioned
2018-01-05T11:53:39Z
dc.date.available
2017-12-16T12:15:17Z
dc.date.available
2018-01-05T11:53:39Z
dc.date.issued
2017-10-05
dc.identifier.issn
0950-9232
dc.identifier.issn
1476-5594
dc.identifier.other
10.1038/onc.2017.146
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/221821
dc.identifier.doi
10.3929/ethz-b-000221821
dc.description.abstract
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.
en_US
dc.language.iso
en
en_US
dc.publisher
Springer Nature
en_US
dc.rights.uri
http://creativecommons.org/licenses/by-nc-sa/4.0/
dc.subject
CNS cancer
en_US
dc.subject
Biomarkers
en_US
dc.title
ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International
dc.date.published
2017-05-29
ethz.journal.title
Oncogene
ethz.journal.volume
36
en_US
ethz.journal.issue
40
en_US
ethz.pages.start
5593
en_US
ethz.pages.end
5608
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.publication.place
Basingstoke
en_US
ethz.publication.status
published
en_US
ethz.date.deposited
2017-12-16T12:15:34Z
ethz.source
WOS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2018-01-05T11:53:46Z
ethz.rosetta.lastUpdated
2019-02-02T14:03:18Z
ethz.rosetta.versionExported
true
ethz.COinS
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