Abstract 1689: The cytoprotective role of the UPR during c-Myc dependent transformation and tumor progression.

Abstract The Unfolded Protein Response (UPR) is a conserved cellular adaptation program that is elicited due to the accumulation of unfolded proteins in the endoplasmic reticulum (ER). The PERK-pEIF2A-ATF4 arm of UPR is triggered by ER stress and primarily serves in the global attenuation of protein translation, and promotes cell survival via selective upregulation of stress induced genes. We recently showed that oncogenic Myc activation initiates UPR due to the accumulation of unfolded proteins in the ER. Using multiple genetic models, we demonstrated that ablation of UPR signaling leads to decreased cell survival in vitro and reduced tumor growth in vivo. The proto-oncogene c-Myc has been shown to activate both pro-tumorigenic and anti-tumorigenic pathways. In c-Myc driven cancers, the pro-apoptotic state is bypassed via a yet undefined pro-survival mechanism. We are interested in elucidating the role of UPR in promoting activation of pro-survival pathways during c-Myc induced tumorigenesis. We previously demonstrated that autophagy, one such pro-survival pathway, is induced and sustained during c-Myc activation in a PERK dependent manner. Moreover, genetic and pharmacological inhibition of autophagy in c-Myc induced cells decreases cell survival. Using a Qiagen Autophagy PCR Array system we screened for autophagy genes that were differentially expressed in a c-Myc dependent manner. Preliminary results indicate that several genes that regulate different steps of autophagy such as ATG9b, ATG5 and ATG16L1 are upregulated upon c-Myc induction, which was validated by qPCR. In PERK-/- MEFs, ATG5 and ATG16L1 were not upregulated and LC3B processing, a marker of autophagy induction, was significantly attenuated upon c-Myc activation. This indicates that PERK is required for the induction of autophagy genes upon c-Myc activation. To further investigate the role of the PERK-pEIF2A-ATF4 arm of UPR in cell survival during c-Myc induction, we looked at the transcription factor ATF4 which is a major downstream mediator of PERK. Using ATF4-/- MEFs, we observed significant cell death and decreased clonogenic survival upon c-Myc activation compared to ATF4+/+ MEFs. We are currently investigating how ATF4 is mediating cell survival during c-Myc induction. Our findings establish that UPR plays as an activator of pro-survival pathways such as autophagy and therefore UPR can be targeted as a therapy modality in c-Myc driven cancers. This research is supported by NIH grant 5R01CA139362-04 Citation Format: Feven Tameire, Lori S. Hart, Bo Qiu, Constantinos Koumenis. The cytoprotective role of the UPR during c-Myc dependent transformation and tumor progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1689. doi:10.1158/1538-7445.AM2013-1689