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.
Insights
Activating transcription factor 4 (ATF4) protects cancer cells from anoikis and metastasis by inducing heme oxygenase 1 (HO-1). Targeting ATF4 and HO-1 may offer new cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- The integrated stress response (ISR) is crucial for cancer cell survival and tumor progression.
- Activating transcription factor 4 (ATF4) is a key mediator of the ISR.
- Targeting the ISR and its effectors can inhibit tumor growth.
Purpose of the Study:
- To investigate the role of ATF4 in anoikis and tumor metastasis.
- To elucidate the mechanism by which ATF4 confers resistance to anoikis.
- To determine the therapeutic potential of targeting ATF4 and its downstream effectors.
Main Methods:
- Utilized human fibrosarcoma cells and a murine lung colonization model.
- Assessed the impact of ATF4 deficiency on anoikis and metastasis.
- Analyzed the transcriptional regulation of heme oxygenase 1 (HO-1) by ATF4 and NRF2.
- Quantified HO-1 expression in human tumor tissues.
Main Results:
- ATF4 protects cancer cells against anoikis and promotes tumor metastasis.
- ATF4 activates a cytoprotective program including autophagy and antioxidant responses, notably inducing HO-1.
- HO-1 upregulation results from the convergence of ATF4 and NRF2 on the HO1 promoter, reducing oxidative stress and cell death.
- ATF4-deficient cells showed impaired lung colonization, which was rescued by reconstituting ATF4 or HO-1.
- HO-1 expression is elevated in human tumors and correlates with reduced patient survival.
Conclusions:
- Heme oxygenase 1 (HO-1) mediates ATF4-dependent anoikis resistance and tumor metastasis.
- ATF4 and HO-1 are promising therapeutic targets for solid tumors.
- Understanding the ISR pathway offers avenues for novel cancer treatments.
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