HMGB1 released by irradiated tumor cells promotes living tumor cell proliferation via paracrine effect

He, Sijia; Cheng, Jin; Sun, Lianhui; Wang, Yiwei; Wang, Chuangui; Liu, Xinjian; Zhang, Zhengxiang; Zhao, Minghui; Luo, Yu; Tian, Ling; Li, Chuan-Yuan; Huang, Qian

doi:10.1038/s41419-018-0626-6

Cited by 80 publications

(85 citation statements)

References 29 publications

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“…In addition to promoting cancer cell death directly, inhibiting HMGB1 with sivelestat could also have additional paracrine effects in cancer. HMGB1 released from dying cells following injury like radiation or chemotherapy could stimulate proliferation of living cells via an apoptosis-stimulated tumor repopulation mechanism named the "Phoenix Rising" pathway (38,39). Inhibition of HMGB1, either with the small-molecule inhibitor glycyrrhizin or by deletion of HMGB1 expression and function with CRISPR/Cas9 technology, abrogated proliferation of living cancer cells through reduction of phospho-ERK activation (39).…”

Section: Discussionmentioning

confidence: 99%

“…HMGB1 released from dying cells following injury like radiation or chemotherapy could stimulate proliferation of living cells via an apoptosis-stimulated tumor repopulation mechanism named the "Phoenix Rising" pathway (38,39). Inhibition of HMGB1, either with the small-molecule inhibitor glycyrrhizin or by deletion of HMGB1 expression and function with CRISPR/Cas9 technology, abrogated proliferation of living cancer cells through reduction of phospho-ERK activation (39). We show that sivelestat markedly reduced extracellular release of HMGB1 into culture media and reduced phospho-ERK activity by up to 3-fold as quantified using flow cytometric analysis and Western blot analysis.…”

Section: Discussionmentioning

confidence: 99%

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Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome

Kam

Piryani

McCall

et al. 2019

Clinical Cancer Research

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Purpose: Myelodysplastic syndrome (MDS) is associated with a dysregulated innate immune system. The purpose of this study was to determine whether modulation of the innate immune system via high mobility group box-1 (HMGB1) could reduce cell viability in MDS.Experimental Design: We quantified HMGB1 in an MDS cell line MDS-L and in primary MDS cells compared with nonmalignant hematopoietic cells. We performed loss-offunction studies of HMGB1 using pooled siRNAs and a small-molecule inhibitor sivelestat compared with standard chemotherapy. We measured levels of engraftment of MDS-L cells in NOD-scidIL2Rg null (NSG) mice following treatment with sivelestat. Mechanistically, we interrogated cell survival pathways and 45 targets within the NFkB pathway using both protein analysis and a proteome profiler array.Results: We discovered that HMGB1 had increased expression in both MDS-L cells and in primary CD34 þ MDS cells compared with healthy CD34 þ hematopoietic cells. Sivelestat impaired MDS cell expansion, increased cellular death, and spared healthy hematopoietic cells. MDS-L marrow engraftment is reduced significantly at 17 weeks following treatment with sivelestat compared with control mice. Treatment of CD34 þ MDS cells with sivelestat and azacitidine or decitabine was additive to increase apoptotic cell death compared with chemotherapy alone. Sivelestat promoted apoptosis with increased expression of PUMA, activated caspase 3, and increased DNA double-strand breaks. Inhibition of HMGB1 reduced levels of Toll-like receptors (TLR) and suppressed activation of NFkB in MDS-L cells.Conclusions: Inhibition of HMGB1 could promote MDS cell death and alter innate immune responses via suppression of NFkB pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome

Kam

Piryani

McCall

et al. 2019

Clinical Cancer Research

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“…The airway epithelium acts as the first line of defense against inhaled allergens including HDM. We have previously shown that HDM sensitization triggers the nuclear-to-cytoplasmic translocation of epithelial alarmin HMGB1 and that this event is regulated by the sequential activation of toll-like receptor 4 (TLR4) and receptor for advanced WT [28][29][30] and hence, the suppression of SRC kinases by the PAG1-CSK complex represents another mechanism through which PAG1 might limit the translocation and release of epithelial-derived HMGB1. Further studies are required to confirm these hypotheses.…”

Section: Discussionmentioning

confidence: 99%

PAG1 limits allergen‐induced type 2 inflammation in the murine lung

Ullah

Vicente

Collinson

et al. 2019

Allergy

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Background Phosphoprotein associated with glycosphingolipid‐enriched microdomains 1 (PAG1) is a transmembrane adaptor protein that affects immune receptor signaling in T and B cells. Evidence from genome‐wide association studies of asthma suggests that genetic variants that regulate the expression of PAG1 are associated with asthma risk. However, it is not known whether PAG1 expression is causally related to asthma pathophysiology. Here, we investigated the role of PAG1 in a preclinical mouse model of house dust mite (HDM)‐induced allergic sensitization and allergic airway inflammation. Methods Pag1‐deficient (Pag1−/−) and wild‐type (WT) mice were sensitized or sensitized/challenged to HDM, and hallmark features of allergic inflammation were assessed. The contribution of T cells was assessed through depletion (anti‐CD4 antibody) and adoptive transfer studies. Results Type 2 inflammation (eosinophilia, eotaxin‐2 expression, IL‐4/IL‐5/IL‐13 production, mucus production) in the airways and lungs was significantly increased in HDM sensitized/challenged Pag1−/− mice compared to WT mice. The predisposition to allergic sensitization was associated with increased airway epithelial high‐mobility group box 1 (HMGB1) translocation and release, increased type 2 innate lymphoid cells (ILC2s) and monocyte‐derived dendritic cell numbers in the mediastinal lymph nodes, and increased T‐helper type 2 (TH2)‐cell differentiation. CD4+ T‐cell depletion studies or the adoptive transfer of WT OVA‐specific CD4+ T cells to WT or Pag1−/− recipients demonstrated that the heightened propensity for TH2‐cell differentiation was both T cell intrinsic and extrinsic. Conclusion PAG1 deficiency increased airway epithelial activation, ILC2 expansion, and TH2 differentiation. As a consequence, PAG1 deficiency predisposed toward allergic sensitization and increased the severity of experimental asthma.

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“…HMGB1 coupled with Stat3 and may contributed to the timely effective Stat3 activation. These processes may predominantly have promoted activation of NFkB/Cox2‐mediated immunity against the “struggling‐to‐survive” and possibly escape elimination or arrest by the pro‐apoptotic mediators .…”

Section: Discussionmentioning

confidence: 99%

HMGB1 knock‐down promoting tumor cells viability and arrest pro‐apoptotic proteins via Stat3/NFκB in HepG2 cells

Alduais

et al. 2018

BioFactors

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Background/Aim: High mobility group box 1 protein (HMGB1) is functionally dynamic and pleiotropic molecule, it has the potential to promote both cell survival and death by regulating multiple signaling pathways, including inflammation and apoptosis. This study aimed at investigating the role of silencing HMGB1 on tumor cells apoptosis and pro-inflammatory proteins expression in hepatocellular HepG2 cancer cells. Methods: HepG2 cells was transfected with si-RNA HMGB1, and the effect on pro-apoptotic proteins expressions like Bax, Bcl2, and pro-inflammatory cytokines like, p65-NFκB, and Cyclooxygenase-2 (Cox2) was assessed using western blot, and also cells apoptosis and proliferation was assessed using annexin V FITC and Calcien AM expression in flow cytometry and fluorescence. Results: HMGB1 silencing was found significantly increase tumor cells viability with significant decrease of pro-apoptotic proteins, also antiapoptotic protein Bcl2 was significantly up-regulated, which suggests a possible role in restricting apoptosis. Furthermore, HMGB1 knocked down found to inhibit Stat3 phosphorylation and significantly affect NFkB p65/Cox2 expression which suggests a link between HMGB1 and Stat3 activation. Our results revealed that HMGB1 knocked down may suppress cells apoptosis and enhance HepG2 cells viability via NFkB/Cox2 and Stat3. © 2018 BioFactors, 44(6):570-576, 2018 Keywords: HMGB1 knock down; NFκB; STAT3, Cox2Abbreviations: Cox2, Cyclooxygenase-2; HMGB1, High mobility group box 1 protein; NAC, N-acetyl-L-cysteine; NFκB, nuclear factor kappa B; Stat3, Signal transducer and activator of transcription 3

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HMGB1 released by irradiated tumor cells promotes living tumor cell proliferation via paracrine effect

Cited by 80 publications

References 29 publications

Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome

Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome

PAG1 limits allergen‐induced type 2 inflammation in the murine lung

HMGB1 knock‐down promoting tumor cells viability and arrest pro‐apoptotic proteins via Stat3/NFκB in HepG2 cells

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