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C-Jun N-terminal kinases are required for oncolytic adenovirus-mediated autophagy

Oncogene volume 34, pages 5295–5301 (2015)Cite this article

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Abstract

Oncolytic adenoviruses, such as Delta-24-RGD (Δ24RGD), are replication-competent viruses that are genetically engineered to induce selective cancer cell lysis. In cancer cells, Δ24RGD induces massive autophagy, which is required for efficient cell lysis and adenoviral spread. Understanding the cellular mechanisms underlying the regulation of autophagy in cells treated with oncolytic adenoviruses may provide new avenues to improve the therapeutic effect. In this work, we showed that cancer cells infected with Δ24RGDundergo autophagy despite the concurrent activation of the AKT/mTOR pathway. Moreover, adenovirus replication induced sustained activation of JNK proteins in vitro. ERK1/2 phosphorylation remained unchanged during adenoviral infection, suggesting specificity of JNK activation. Using genetic ablation and pharmacological inactivation of JNK, we unequivocally demonstrated that cells infected with Δ24RGD required JNK activation. Thus, genetic co-ablation of JNK1 and JNK2 genes or inhibition of JNK kinase function rendered Δ24RGD–treated cells resistant to autophagy. Accordingly, JNK activation induced phosphorylation of Bcl-2 and prevented the formation of Bcl-2/Beclin 1 autophagy suppressor complexes. Using an orthotopic model of human glioma xenograft, we showed that treatment with Δ24RGD induced phosphorylation and nuclear translocation of JNK, as well as phosphorylation of Bcl-2. Collectively, our data identified JNK proteins as an essential mechanistic link between Δ24RGD infection and autophagy in cancer cells. Activation of JNK without inactivation of the AKT/mTOR pathway constitutes a distinct molecular signature of autophagy regulation that differentiates Δ24RGD adenovirus from the mechanism used by other oncolytic viruses to induce autophagy and provides a new rationale for the combination of oncolytic viruses and chemotherapy.

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Acknowledgements

We thank Tamara Locke (Department of Scientific Publications, The University of Texas MD Anderson Cancer Center) for editorial assistance. This work was supported by grants from the NHI/NCI (P50CA127001; Cancer Center Support Grant P30CA016672—High Resolution Electron Microscopy and Research Animal Support Facilities), the Marnie Rose Foundation, the Will Power Foundation, the Schissler Foundation and the American Legion Auxiliary.

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Authors and Affiliations

  1. Department of Neuro-Oncology, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    S R Klein, S Piya, Z Lu, Y Xia, E J White, C Gomez-Manzano, H Jiang & J Fueyo

  2. Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA

    S R Klein, Z Lu & C Gomez-Manzano

  3. Department of Medical Oncology, University Hospital of Navarra, Pamplona, Spain

    M M Alonso

  4. Department of Neurosurgery, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J Wei & J Fueyo

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  1. S R Klein
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Correspondence to J Fueyo.

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Competing interests

Dr Fueyo and Dr Gomez-Manzano are funders of DNAtrix Inc., a company with interest in the clinical development of Delta-24-RGD as a therapeutic tool.

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Klein, S., Piya, S., Lu, Z. et al. C-Jun N-terminal kinases are required for oncolytic adenovirus-mediated autophagy. Oncogene 34, 5295–5301 (2015). https://doi.org/10.1038/onc.2014.452

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