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.
Source:
ER stress-mediated autophagy promotes Myc-dependent transformation and
tumor growth. Hart LS, Cunningham JT, Datta T, Dey S, Tameire F, Lehman SL, Qiu
B, Zhang H, Cerniglia G, Bi M, Li Y, Gao Y, Liu H, Li C, Maity A,
Thomas-Tikhonenko A, Perl AE, Koong A, Fuchs SY, Diehl JA, Mills IG, Ruggero D,
Koumenis C (koumenis@xrt.upenn.edu).
J Clin Invest. 2012 Nov 12. pii: 62973.
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