HMGB1 release and redox regulates autophagy and apoptosis in cancer cells

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

Research output: Contribution to journalArticle

270 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5299-5310
Number of pages12
JournalOncogene
Volume29
Issue number38
DOIs
Publication statusPublished - Sep 23 2010
Externally publishedYes

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Keywords

  • apoptosis
  • autophagy
  • Beclin 1
  • chemotheraphy
  • HMGB1
  • redox

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Tang, D., Kang, R., Cheh, C. W., Livesey, K. M., Liang, X., Schapiro, N. E., ... Lotze, M. T. (2010). HMGB1 release and redox regulates autophagy and apoptosis in cancer cells. Oncogene, 29(38), 5299-5310. https://doi.org/10.1038/onc.2010.261