Abstract A34: The stress response transcription factor ATF4 mediates cytoprotective pathways in c-Myc overexpressing cells

The proto-oncogene c-Myc is often deregulated in human tumors and its overexpression associates with poor prognosis in patients. While c-Myc is a potent activator of pro-tumorigenic pathways, it can also induce anti-tumorgenic pathways such as apoptosis. However, in c-Myc driven cancers the anti-tumorigenic state is evaded via a yet poorly understood pro-survival mechanism. We previously reported that activation of the PERK arm of the Unfolded Protein Response (UPR) is one such pro-survival mechanism induced by c-Myc to bypass c-Myc induced apoptosis. We also demonstrated enhanced activation of the PERK/p-eIF2α arm of the UPR in a mouse model of lymphoma and in B-cells from human lymphoma patients compared to normal tissues. ATF4, one of the main downstream effectors of PERK, regulates amino acid metabolism, antioxidant response and autophagy. Using the CRISPR/CAS9 genome-editing tool we were able to ablate portions of the ATF4 gene in DLD-1, human colon carcinoma cell line, preventing ATF4 protein expression. Here, we show ATF4 expression is induced in Myc overexpressing ATF4-WT DLD-1 cells. Activation of c-Myc in ATF4-deficient DLD-1 cells resulted in decreased clonogenic survival and reduced autophagy. Addition of Trolox, an antioxidant, conferred protection in ATF4 deficient cells. These findings indicate that the transcription factor ATF4 activates pro-survival pathways such as antioxidant response and autophagy during c-Myc overexpression to promote survival. Therefore, therapeutically targeting these pathways would switch the balance towards cell death in c-Myc dependent tumors. Citation Format: Feven Tameire Tameire, Costas Koumenis. The stress response transcription factor ATF4 mediates cytoprotective pathways in c-Myc overexpressing cells. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A34.