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

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

来源：Journal of Clinical Investigation, 2012, 122(12): 4621-4634.

DOI：10.1172/JCI62973

• ENDOPLASMIC-RETICULUM STRESS
• UNFOLDED PROTEIN RESPONSE
• C-MYC
• RIBOSOME BIOGENESIS
• MESSENGER-RNA
• MOUSE MODEL
• TRANSLATION
• CANCER
• PERK
• ACTIVATION

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/eIF2 alpha/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.

• 出版日期2012-12