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A JNK-mediated autophagy pathway that triggers c-IAP degradation and necroptosis for anticancer chemotherapy

Oncogene volume 33, pages 3004–3013 (2014)Cite this article

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Abstract

Killing cancer cells through the induction of apoptosis is one of the main mechanisms of chemotherapy. However, numerous cancer cells have primary or acquired apoptosis resistance, resulting in chemoresistance. In this study, using a novel chalcone derivative chalcone-24 (Chal-24), we identified a novel anticancer mechanism through autophagy-mediated necroptosis (RIP1- and RIP3-dependent necrosis). Chal-24 potently killed different cancer cells with induction of necrotic cellular morphology while causing no detectable caspase activation. Blocking the necroptosis pathway with either necrostatin-1 or by knockdown of RIP1 and RIP3 effectively blocked the cytotoxicity of Chal-24, suggesting that Chal-24-induced cell death is associated with necroptosis. Chal-24 robustly activated JNK and ERK and blockage of which effectively suppressed Chal-24-induced cytotoxicity. In addition, Chal-24 strongly induced autophagy that is dependent on JNK-mediated phosphorylation of Bcl-2 and Bcl-xL and dissociation of Bcl-2 or Bcl-xL from Beclin-1. Importantly, suppression of autophagy, with either pharmacological inhibitors or small interfering RNAs targeting the essential autophagy components ATG7 and Beclin-1, effectively attenuated Chal-24-induced cell death. Furthermore, we found that autophagy activation resulted in c-IAP1 and c-IAP2 degradation and formation of the Ripoptosome that contributes to necroptosis. These results thus establish a novel mechanism for killing cancer cells that involves autophagy-mediated necroptosis, which may be employed for overcoming chemoresistance.

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Acknowledgements

This study was partly supported by grants from NIEHS/NIH (R01ES017328), NCI/NIH (R03CA156301), Chongqing Health Bureau (2012–2–001).

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Author notes

  1. W He and Q Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, NM, Albuquerque, USA

    W He, Q Wang, J Xu, M T Padilla, Z Li, Y Liu & Y Lin

  2. Department of Urology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China

    W He & X Gou

  3. Laboratory of Molecular and Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu, China

    Q Wang & X Wang

  4. Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA

    B Srinivasan & C Xing

  5. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    H-M Shen

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Correspondence to C Xing or Y Lin.

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He, W., Wang, Q., Srinivasan, B. et al. A JNK-mediated autophagy pathway that triggers c-IAP degradation and necroptosis for anticancer chemotherapy. Oncogene 33, 3004–3013 (2014). https://doi.org/10.1038/onc.2013.256

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  • DOI: https://doi.org/10.1038/onc.2013.256

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