ER stress–mediated autophagy promotes Myc-dependent transformation and tumor growth
Lori S. Hart, … , Davide Ruggero, Constantinos Koumenis
Lori S. Hart, … , Davide Ruggero, Constantinos Koumenis
Published November 12, 2012
Citation Information: J Clin Invest. 2012;122(12):4621-4634. https://doi.org/10.1172/JCI62973.
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Research Article Oncology

ER stress–mediated autophagy promotes Myc-dependent transformation and tumor growth

Abstract

The proto-oncogene c-Myc paradoxically activates both proliferation and apoptosis. In the pathogenic state, c-Myc–induced apoptosis is bypassed via a critical, yet poorly understood escape mechanism that promotes cellular transformation and tumorigenesis. The accumulation of unfolded proteins in the ER initiates a cellular stress program termed the unfolded protein response (UPR) to support cell survival. Analysis of spontaneous mouse and human lymphomas demonstrated significantly higher levels of UPR activation compared with normal tissues. Using multiple genetic models, we demonstrated that c-Myc and N-Myc activated the PERK/eIF2α/ATF4 arm of the UPR, leading to increased cell survival via the induction of cytoprotective autophagy. Inhibition of PERK significantly reduced Myc-induced autophagy, colony formation, and tumor formation. Moreover, pharmacologic or genetic inhibition of autophagy resulted in increased Myc-dependent apoptosis. Mechanistically, we demonstrated an important link between Myc-dependent increases in protein synthesis and UPR activation. Specifically, by employing a mouse minute (L24+/–) mutant, which resulted in wild-type levels of protein synthesis and attenuation of Myc-induced lymphomagenesis, we showed that Myc-induced UPR activation was reversed. Our findings establish a role for UPR as an enhancer of c-Myc–induced transformation and suggest that UPR inhibition may be particularly effective against malignancies characterized by c-Myc overexpression.

Authors

Lori S. Hart, John T. Cunningham, Tatini Datta, Souvik Dey, Feven Tameire, Stacey L. Lehman, Bo Qiu, Haiyan Zhang, George Cerniglia, Meixia Bi, Yan Li, Yan Gao, Huayi Liu, Changhong Li, Amit Maity, Andrei Thomas-Tikhonenko, Alexander E. Perl, Albert Koong, Serge Y. Fuchs, J. Alan Diehl, Ian G. Mills, Davide Ruggero, Constantinos Koumenis

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Figure 6

UPR activation in human lymphomas.

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UPR activation in human lymphomas. (A) Primary human B cells, obtained f...
(A) Primary human B cells, obtained from lymphoma patients and normal donors, were analyzed for UPR activation by p-eIF2α and p-PERK (Ser713) levels (*samples with Myc translocation confirmed by FISH analysis [note: Myc translocation was confirmed for patient 1566, who was diagnosed with AML]; all other samples were confirmed for Burkitt’s lymphoma morphology and are presumed to contain Myc translocations). (B) Primary human B cell samples were analyzed for downstream UPR activation by qPCR of XBP1s and ATF3 (average of 3 independent qPCR reactions). (C) An ER stress response signature clusters c-Myc–overexpressing B cell lymphomas. Raw data were downloaded from the NCBI GEO repository (GSE4475). The genes listed were derived from an ER stress response signature defined using ER stressors and genetic knockouts by Harding et al. (49). Normalized probe signals for the genes listed were clustered using a Pearson complete correlation coefficient, with a significance threshold for each hierarchical subcluster set at P < 0.05. Cases annotated as Ig-Myc were defined as such by fluorescence in situ hybridization in the original expression array study. Expression signals are depicted using pseudocoloring, in which expression for each gene is shown as high (red) or low (green).