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Mol Cancer Res. 2019 Sep 24. pii: molcanres.0245.2019. doi: 10.1158/1541-7786.MCR-19-0245. [Epub ahead of print]

Adaptive protein translation by the integrated stress response maintains the proliferative and migratory capacity of lung adenocarcinoma cells.

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Cell Biology, Yale University.
Pathology, Yale School of Medicine.
Department of Pathology, Yale University.
Pathology, Yale University.
Internal Medicine, Yale School of Medicine.
Cell Biology, Yale School of Medicine.
Pathology, Yale School of Medicine


The integrated stress response (ISR) is a conserved pathway which is activated by cells that are exposed to stress. In lung adenocarcinoma (LUAD), activation of the ATF4 branch of the ISR by certain oncogenic mutations has been linked to the regulation of amino acid metabolism. In the present study, we provide evidence for ATF4 activation across multiple stages and molecular subtypes of human LUAD. In response to extracellular amino acid limitation, LUAD cells with diverse genotypes commonly induce ATF4 in an eIF2α dependent manner, which can be blocked pharmacologically using the integrated stress response inhibitor (ISRIB). Although suppressing eIF2α or ATF4 can trigger different biological consequences, adaptive cell cycle progression and cell migration are particularly sensitive to inhibition of the ISR. These phenotypes require the ATF4 target gene asparagine synthetase (ASNS), which maintains protein translation independently of the mTOR/PI3K pathway. Moreover, NRF2 protein levels and oxidative stress can be modulated by the ISR downstream of ASNS. Finally, we demonstrate that ASNS controls the biosynthesis of select proteins, including the cell cycle regulator cyclin B1, which are associated with poor LUAD patient outcome. Our findings uncover new regulatory layers of the ISR pathway and its control of proteostasis in lung cancer cells. Implications: We reveal novel regulatory mechanisms by which the integrated stress response controls selective protein translation and is required for cell cycle progression and migration of lung cancer cells.

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