The DOI matches its Crossref record; 69 of the 69 references it cites were found in a registry or an index.
ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis
Open accessAbstract
The integrated stress response (ISR) is a critical mediator of cancer cell survival, and targeting the ISR inhibits tumor progression. Here, we have shown that activating transcription factor 4 (ATF4), a master transcriptional effector of the ISR, protects transformed cells against anoikis - a specialized form of apoptosis - following matrix detachment and also contributes to tumor metastatic properties. Upon loss of attachment, ATF4 activated a coordinated program of cytoprotective autophagy and antioxidant responses, including induced expression of the major antioxidant enzyme heme oxygenase 1 (HO-1). HO-1 upregulation was the result of simultaneous activation of ATF4 and the transcription factor NRF2, which converged on the HO1 promoter. Increased levels of HO-1 ameliorated oxidative stress and cell death. ATF4-deficient human fibrosarcoma cells were unable to colonize the lungs in a murine model, and reconstitution of ATF4 or HO-1 expression in ATF4-deficient cells blocked anoikis and rescued tumor lung colonization. HO-1 expression was higher in human primary and metastatic tumors compared with noncancerous tissue. Moreover, HO-1 expression correlated with reduced overall survival of patients with lung adenocarcinoma and glioblastoma. These results establish HO-1 as a mediator of ATF4-dependent anoikis resistance and tumor metastasis and suggest ATF4 and HO-1 as potential targets for therapeutic intervention in solid tumors.
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Cited by
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680
Hayes, J. D., Dinkova-Kostova, A. T., & Tew, K. D. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.06.001 · Cited by 2,654
Endoplasmic reticulum stress signals in the tumour and its microenvironment
Chen, X., & Cubillos-Ruiz, J. R. (2021) · Nature Reviews Cancer · doi:10.1038/s41568-020-00312-2 · Cited by 1,356
Oxidative stress inhibits distant metastasis by human melanoma cells
Piskounova, E., Agathocleous, M., Murphy, M. M., Hu, Z., Huddlestun, S. E., Zhao, Z., Leitch, A. M., Johnson, T. M., DeBerardinis, R. J., & Morrison, S. J. (2015) · Nature · doi:10.1038/nature15726 · Cited by 1,269
Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer
Cubillos-Ruiz, J. R., Bettigole, S. E., & Glimcher, L. H. (2017) · Cell · doi:10.1016/j.cell.2016.12.004 · Cited by 895
Metadata
- Authors
- Dey, S., Sayers, C. M., Verginadis, I. I., Lehman, S. L., Cheng, Y., Cerniglia, G. J., Tuttle, S. W., Feldman, M. D., Zhang, P. J. L., Fuchs, S. Y., Diehl, J. A., & Koumenis, C.
- Venue
- Journal of Clinical Investigation
- Published
- 2015-05-26
- Volume
- 125
- Issue
- 7
- Pages
- 2592-2608
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W1531386034
- Cited by
- 282
- References
- 69
- FWCI
- 10.42
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Dey, S., Sayers, C. M., Verginadis, I. I., Lehman, S. L., Cheng, Y., Cerniglia, G. J., Tuttle, S. W., Feldman, M. D., Zhang, P. J. L., Fuchs, S. Y., Diehl, J. A., & Koumenis, C. (2015). ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis. Journal of Clinical Investigation. https://doi.org/10.1172/jci78031
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