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 DiehlIan G Mills, Davide Ruggero, Constantinos Koumenis

Research output: Contribution to journalArticle

221 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4621-34
Number of pages14
JournalThe Journal of clinical investigation
Volume122
Issue number12
DOIs
Publication statusPublished - Dec 2012

Keywords

  • Animals
  • Apoptosis
  • Autophagy
  • Burkitt Lymphoma
  • Calcium Signaling
  • Caspases
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Cell Transformation, Neoplastic
  • Cluster Analysis
  • Endoplasmic Reticulum Stress
  • Gene Knockout Techniques
  • Heterozygote
  • Humans
  • Mice
  • Oligonucleotide Array Sequence Analysis
  • Proto-Oncogene Proteins c-myc
  • Ribosomal Proteins
  • Transcriptome
  • Unfolded Protein Response
  • eIF-2 Kinase

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  • Cite this

    Hart, L. S., Cunningham, J. T., Datta, T., Dey, S., Tameire, F., Lehman, S. L., Qiu, B., Zhang, H., Cerniglia, G., Bi, M., Li, Y., Gao, Y., Liu, H., Li, C., Maity, A., Thomas-Tikhonenko, A., Perl, A. E., Koong, A., Fuchs, S. Y., ... Koumenis, C. (2012). ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth. The Journal of clinical investigation, 122(12), 4621-34. https://doi.org/10.1172/JCI62973