Abstract SY06-02: Activation of the UPR by c-Myc promotes transformation and tumorigenesis via cytoprotective autophagy
Authors: Constantinos Koumenis, Haiyan Zhang, Meixia Bi, Stacey L. Lehman, Tatini Datta, Huayi Liu, Andrei Thomas-Tikhonenko, Albert Koong, Serge Y. Fuchs, J. Alan Diehl, Davide Ruggero
Journal: Cancer Research (2011)

Abstract The Unfolded Protein Response (UPR) is a cellular homeostatic program initiated by an excess of unfolded/misfolded client proteins in the Endoplasmic Reticulum (ER) lumen, with a primarily cytoprotective effect. We have previously shown that tumor cell survival under hypoxic and nutrient deprivation stress is dependent on the ER resident protein and UPR effector PERK since the growth of PERK-null tumors is significantly inhibited in vivo. PERK deficient tumors are unable to tolerate ER stress induced by microenvironmental challenges such as hypoxia, and therefore, the tumors are unable to grow as ER-stress-induced apoptosis is induced. Similar findings have been confirmed for tumors lacking XBP1 (Romero-Ramirez et al). In addition to microenvironmental stresses such as hypoxia, oncogenes are known to activate cellular stress responses, including metabolic stress, apoptosis, DNA damage responses, and cellular senescence. MYC is the target of chromosomal translocation or gene amplification during the development of many human cancers. Most notably, almost every case of Burkitt's lymphoma involves the translocation of the MYC proto-oncogene to the enhancer region of the heavy or light chain immunoglobulin loci resulting in the constitutive overexpression of c-Myc in B lymphocytes. c-Myc expression has been associated with a two-fold increase in both total cellular proteins and the rates of protein synthesis in the Eµ-myc mouse model. This finding raises the possibility that c-Myc-transformed cells are exposed to a higher than normal level of ER stress. Therefore, we hypothesized that the increase in protein burden in cells overexpressing c-Myc corresponds to increased ER stress and activation of the UPR. Using multiple genetic models of regulated c-Myc and N-Myc activation, we demonstrate that Myc activates the PERK/eIF2α/Atf4 arm of the UPR. Activation of UPR leads to increased cell survival via the induction of cytoprotective autophagy as evidenced by upregulated LC3 processing, p62 degradation and increased double-membraned autophagosomes when analyzed by electron microscopy. Ablation of PERK significantly reduced Myc-induced autophagy, cell transformation and tumor formation in nude mice. Samples from Eμ-Myc mice and human lymphomas demonstrate higher levels of UPR activation (eIF2α phosphorylation and XBP1 splicing) compared to corresponding normal tissues and B-cells. Mechanistically, we genetically demonstrate an important link between Myc-dependent increases in protein synthesis and UPR activation. Specifically, by employing a mouse minute, which results in wild-type levels of protein synthesis and attenuation of Myc-induced lymphomagenesis, we show that Myc-induced UPR activation is reversed. Our findings establish a novel role of UPR activation as an enhancer of c-Myc-induced transformation and suggest that inhibition of the UPR may be particularly effective against malignancies characterized by c-Myc overexpression. The identification of cellular stress response pathways activated by c-Myc represents an opportunity to exploit such pathways in the development of novel therapeutics targeting oncogene-dependent malignancies. Supported by NCI grants CA94214 and CA 139362 to C.K. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY06-02. doi:10.1158/1538-7445.AM2011-SY06-02