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PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage

Oncogene volume 29, pages 3881–3895 (2010)Cite this article

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Abstract

To proliferate and expand in an environment with limited nutrients, cancer cells co-opt cellular regulatory pathways that facilitate adaptation and thereby maintain tumor growth and survival potential. The endoplasmic reticulum (ER) is uniquely positioned to sense nutrient deprivation stress and subsequently engage signaling pathways that promote adaptive strategies. As such, components of the ER stress-signaling pathway represent potential antineoplastic targets. However, recent investigations into the role of the ER resident protein kinase, RNA-dependent protein kinase (PKR)-like ER kinase (PERK) have paradoxically suggested both pro- and anti-tumorigenic properties. We have used animal models of mammary carcinoma to interrogate the contribution of PERK in the neoplastic process. The ablation of PERK in tumor cells resulted in impaired regeneration of intracellular antioxidants and accumulation of reactive oxygen species triggering oxidative DNA damage. Ultimately, PERK deficiency impeded progression through the cell cycle because of the activation of the DNA damage checkpoint. Our data reveal that PERK-dependent signaling is used during both tumor initiation and expansion to maintain redox homeostasis, thereby facilitating tumor growth.

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Acknowledgements

We thank Serge Fuchs for critical reading of the paper, Margarita Romero for outstanding technical assistance and the AFCRI histology core. This work was supported by the National Institutes of Health Grants F32CA1238252 (to EBM), P01 CA104838 and a Leukemia & Lymphoma Scholar award (to JAD).

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Authors and Affiliations

  1. The Leonard and Madlyn Abramson Family Cancer Research Institute and Cancer Center, University of Pennsylvania, Philadelphia, PA, USA

    E Bobrovnikova-Marjon, C Grigoriadou, D Pytel, F Zhang & J A Diehl

  2. Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA

    E Bobrovnikova-Marjon, C Grigoriadou, D Pytel, F Zhang & J A Diehl

  3. Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA

    J Ye & C Koumenis

  4. Department of Biology, Penn State University, University Park, PA, USA

    D Cavener

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  1. E Bobrovnikova-Marjon
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Bobrovnikova-Marjon, E., Grigoriadou, C., Pytel, D. et al. PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage. Oncogene 29, 3881–3895 (2010). https://doi.org/10.1038/onc.2010.153

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