ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis
Souvik Dey, … , J. Alan Diehl, Constantinos Koumenis
Souvik Dey, … , J. Alan Diehl, Constantinos Koumenis
Published July 1, 2015; First published May 26, 2015
Citation Information: J Clin Invest. 2015;125(7):2592-2608. https://doi.org/10.1172/JCI78031.
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Research Article Oncology

ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis

Abstract

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.

Authors

Souvik Dey, Carly M. Sayers, Ioannis I. Verginadis, Stacey L. Lehman, Yi Cheng, George J. Cerniglia, Stephen W. Tuttle, Michael D. Feldman, Paul J.L. Zhang, Serge Y. Fuchs, J. Alan Diehl, Constantinos Koumenis

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Figure 6

ATF4 and HO-1 promote fibrosarcoma lung colonization.

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ATF4 and HO-1 promote fibrosarcoma lung colonization. (A) Kaplan-Meier s...
(A) Kaplan-Meier survival analysis for mice injected by tail vein with shNT (n = 4) or shATF4 HT1080 clones (n = 8). ***P = 0.0002, log-rank test. (B) shNT (n = 5), shATF4 (n = 5), and ATF4 overexpressing (shATF4 + Ad-mATF4) HT1080 cells (n = 8) were injected intravenously, and bioluminescent images were obtained. Representative images from 4 hours after injection and 8 weeks after injection are shown. (C) Mean radiance (photon/s/cm2/sr) from the chest/lung area of mice is plotted against time after injection (mean ± SEM). (D) shNT.HT1080 cells along with shATF4.HT1080 cells and HO-1–overexpressing cells (shATF4 + hHO-1) were injected. Mean radiance is plotted as a function of time (mean ± SEM). *P < 0.05; **P < 0.01, Student’s t test. (E) Kaplan-Meier survival analysis for mice injected with shNT.HT1080 (n = 5), shATF4.HT1080 (n = 5), and shATF4+hHO-1.HT1080 (n = 10) cells (*P = 0.0285, log-rank test between groups of mice injected with shATF4.HT1080 and shATF4+hHO-1.HT1080 cells). (F) i-shATF4.HT1080 cells were injected on the right flank in female nude mice, and mice were administered water with or without 1 mg/ml Dox (+Dox, n = 8; –Dox, n = 7). Primary tumors were excised surgically when tumors reached approximately 400 mm3, and bioluminescence from the chest/lung area was measured and plotted over time (days). Data are represented as mean ± SEM. *P < 0.05, Student’s t test.