ER stress–mediated autophagy promotes Myc-dependent transformation and tumor growth
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
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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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 3

Loss of UPR signaling results in c-Myc–induced caspase-dependent apoptosis.

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Loss of UPR signaling results in c-Myc–induced caspase-dependent apoptos...
(A) Perkfl/fl or Perk–/– MEFs infected with control (mig) or mycER–expressing retroviruses were treated with EtOH or 4-HT, and clonogenic survival was assayed (left panel); colonies were counted, and the surviving fraction is presented (right panel) normalized to each untreated control (error bars represent SEM; n = 3; **P < 0.0001, *P < 0.0003). (B) MEFs were treated with 4-HT for 24 hours, followed by immunoblotting for cleaved PARP (c-PARP). (C) mycER:Perk–/– MEFs were treated with 4-HT in the presence or absence of 4-PBA (5 mM), and immunoblotting was performed for cleaved-PARP. (D) S51A-eIF2α knock-in MEFs infected with control (mig) or mycER-expressing retroviruses were treated with ethanol or 4-HT, and survival was assayed (compared with WT MEFs expressing mycER; **P < 0.00002, *P < 0.002, Student’s 2-tailed t test). (E) mycER:Perk–/– MEFs were transfected with CMV control or Bcl-xL–expressing plasmids (WT or ER-targeted cb5), treated with 4-HT, cultured for 72 hours, and stained with crystal violet, and cell survival was quantified (*P < 0.001, Student’s 2-tailed t test).