ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner
Open accessAbstract
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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The ability of ATF4 to upregulate system xc− and stabilize GPX4 upon HSPA5 transactivation is causally involved in some models of oncogenesis and chemoresistance to ferroptosis induction.
“the ability of ATF4 to upregulate system xc− and stabilize GPX4 (upon HSPA5 transactivation) is causally involved in some models of oncogenesis and chemoresistance to ferroptosis induction [580, 599].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [599]
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- Authors
- Chen, D., Fan, Z., Rauh, M., Buchfelder, M., Eyupoglu, I. Y., & Savaskan, N.
- Affiliations
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Corresponding author
- Savaskan, N
- Venue
- Oncogene
- Published
- 2017-05-29
- Volume
- 36
- Issue
- 40
- Pages
- 5593-5608
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC5633655
- OpenAlex
- W2617266043
- Cited by
- 421
- References
- 42
- Citations by year
- 2026: 28 · 2025: 46 · 2024: 77 · 2023: 67 · 2022: 84 · 2021: 49 · 2020: 36 · 2019: 20 · 2018: 11 · 2017: 3
- FWCI
- 15.84
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Oncogene (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by-nc-sa)
- ETH Zürich Research Collection
- Funders
- China Scholarship Council
- RWTH Aachen University
- Universitätsklinikum Erlangen
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- ATF4, system xc-, ferroptosis, glioma, tumor angiogenesis, neuronal cell death, GPX4, RSL3, erastin, sorafenib, cell proliferation, cell migration, anchorage-independent growth, tumor microenvironment, transcriptional regulation
- MeSH terms
- Brain Neoplasms, Glioma, Humans, Iron, Neovascularization, Pathologic, Neurons, Gene Expression Regulation, Neoplastic, Cell Death, Glutamic Acid, Amino Acid Transport System y+, Cell Line, Tumor, Cell Proliferation, Activating Transcription Factor 4
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