Cancer cells fight off stress with ATF4
Cancer cells within a tumor are faced with a variety of stresses, including hypoxia and starvation. Moreover, cancer cells that metastasize from the initial tumor site must prevent activation of anoikis, a specialized cell form of cell death that initiates in response to a loss of contact with the ECM. The transcription factor ATF4 mediates activation of the integrated stress response (ISR) and promotes cancer cell survival. Additionally, ATF4 is upregulated in several tumor types and may contribute to metastatic phenotypes. Souvik Dey, Carly Sayers, and colleagues at the University of Pennsylvania determined that ATF4 protects cancer cells from anoikis and contributes to metastasis. ISR was activated in tumor cells in response to detachment from the ECM, resulting in induction of an ATF4-coordinated program of cytoprotective autophagy and antioxidant responses, including the antioxidant enzyme heme oxygenase 1 (HO-1). Oxidative stress and apoptosis were increased in ATF4-deficent cells; however, reexpression of HO-1 in these cells prevented cell death. Inhibition of ATF4 in human fibrosarcoma cells prevented lung colonization in a murine model, and expression of either ATF4 or HO-1 in these cells restored metastatic phenotypes. Evaluation of primary and metastatic tumors as well as non-cancerous tissue from glioblastoma and lung adenocarcinoma patients revealed that HO-1 is upregulated in tumors, and increased HO-1 was associated with reduced survival. Together, these results indicate that ATF4-mediated induction of HO-1 protects cancer cells from anoikis and promotes metastasis. The accompanying image shows H&E staining of lung sections from mice that received either control (top) or ATF4-deficeint (bottom) human fibrosarcoma cells.
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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
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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