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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 125 Issue 7 Pg. 2592-608 (Jul 01 2015) ISSN: 1558-8238 [Electronic] United States
• PMID: 26011642 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ATF4 protein, human
• Atf4 protein, mouse
• Membrane Proteins
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Nfe2l2 protein, mouse
• Reactive Oxygen Species
• Activating Transcription Factor 4
• HMOX1 protein, human
• Heme Oxygenase-1
• Hmox1 protein, mouse

Topics

• Activating Transcription Factor 4 (antagonists & inhibitors, genetics, metabolism)
• Adenocarcinoma (enzymology, genetics)
• Adenocarcinoma of Lung
• Animals
• Anoikis (genetics, physiology)
• Cell Line, Tumor
• Cell Movement
• Enzyme Induction
• Female
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Glioblastoma (enzymology, genetics)
• Heme Oxygenase-1 (biosynthesis, genetics)
• Heterografts
• Humans
• Lung Neoplasms (enzymology, genetics, metabolism, pathology, secondary)
• Membrane Proteins (biosynthesis, genetics)
• Mice
• Mice, Nude
• NF-E2-Related Factor 2 (antagonists & inhibitors, genetics, metabolism)
• Neoplasm Invasiveness
• Neoplasm Metastasis (genetics, pathology, physiopathology)
• Oxidative Stress
• Reactive Oxygen Species (metabolism)
• Unfolded Protein Response