HMGB1 release and redox regulates autophagy and apoptosis in cancer cells
Open accessAbstract
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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HMGB1 biological activities can switch from pro-inflammatory to anti-inflammatory depending on variables including oxidation state.
“That said, it should be noted that biological activities of HMGB1 may flip from pro-inflammatory to anti-inflammatory depending on multiple variables including its oxidation state [917–923].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [920]
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- Authors
- Tang, D., Kang, R., Cheh, C.-W., Livesey, K. M., Liang, X., Schapiro, N. E., Benschop, R., Sparvero, L. J., Amoscato, A. A., Tracey, K. J., Zeh, H. J., & Lotze, M. T.
- Affiliations
- University of Pittsburgh (US)
- Eli Lilly (United States) (US)
- North Shore University Hospital (US)
- Corresponding author
- Tang, D
- Zeh, H J
- Lotze, M T
- Venue
- Oncogene
- Published
- 2010-07-12
- Volume
- 29
- Issue
- 38
- Pages
- 5299-5310
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC2945431
- OpenAlex
- W2052094075
- Cited by
- 461
- References
- 49
- Citations by year
- 2026: 10 · 2025: 16 · 2024: 12 · 2023: 20 · 2022: 27 · 2021: 33 · 2020: 32 · 2019: 26 · 2018: 36 · 2017: 28 · 2016: 28 · 2015: 33 · 2014: 47 · 2013: 44 · 2012: 35
- FWCI
- 22.49
- Type
- journal article
- Language
- en
- Update notices
- correction (2025-07-24)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Pittsburgh
- National Institutes of Health
- National Cancer Institute (P01CA101944)
- National Institute of General Medical Sciences (R01GM062508)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- HMGB1, HMGB1 release, redox regulation, autophagy, apoptosis, cancer cells, RAGE, Beclin-1, ethyl pyruvate, chemoresistance, alkylating agents, paclitaxel, oxaliplatin, doxorubicin, ultraviolet radiation, caspase-9, caspase-3, mitochondrial apoptosis
- MeSH terms
- Antineoplastic Agents, Autophagy, Neoplasms, Oxidation-Reduction, Apoptosis, HMGB1 Protein
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