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HMGB1 release and redox regulates autophagy and apoptosis in cancer cells

Oncogene volume 29, pages 5299–5310 (2010)Cite this article

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Abstract

The functional relationship and cross-regulation between autophagy and apoptosis is complex. In this study we show that the high-mobility group box 1 protein (HMGB1) is a redox-sensitive regulator of the balance between autophagy and apoptosis. In cancer cells, anticancer agents enhanced autophagy and apoptosis, as well as HMGB1 release. HMGB1 release may be a prosurvival signal for residual cells after various cytotoxic cancer treatments. Diminished HMGB1 by short hairpin RNA transfection or inhibition of HMGB1 release by ethyl pyruvate or other small molecules led predominantly to apoptosis and decreased autophagy in stressed cancer cells. In this setting, reducible HMGB1 binds to the receptor for advanced glycation end products (RAGEs), but not to Toll-like receptor 4, induces Beclin1-dependent autophagy and promotes tumor resistance to alkylators (melphalan), tubulin disrupting agents (paclitaxel), DNA crosslinkers (ultraviolet light) and DNA intercalators (oxaliplatin or adriamycin). On the contrary, oxidized HMGB1 increases the cytotoxicity of these agents and induces apoptosis mediated by the caspase-9/-3 intrinsic pathway. HMGB1 release, as well as its redox state, thus links autophagy and apoptosis, representing a suitable target when coupled with conventional tumor treatments.

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Acknowledgements

This project was funded by a grant from the NIH 1 P01 CA 101944–04 (Michael T. Lotze) integrating NK and DC into Cancer Therapy from the National Cancer Institute. Thoughtful discussions and review of this work with Timothy Billiar and Sarah Berman at the University of Pittsburgh and with external colleagues Guido Kroemer, Douglas Green, Matthew Albert and Beth Levine are much appreciated.

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  1. D Tang and R Kang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, The DAMP Laboratory, Hillman Cancer Center, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA

    D Tang, R Kang, C-W Cheh, K M Livesey, X Liang, N E Schapiro, L J Sparvero, A A Amoscato, H J Zeh & M T Lotze

  2. Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA

    R Benschop

  3. North Shore University Hospital, New York University School of Medicine, Manhasset, NY, USA

    K J Tracey

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Correspondence to D Tang, H J Zeh or M T Lotze.

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Tang, D., Kang, R., Cheh, CW. et al. HMGB1 release and redox regulates autophagy and apoptosis in cancer cells. Oncogene 29, 5299–5310 (2010). https://doi.org/10.1038/onc.2010.261

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