HMGB1: a two-headed signal regulating tumor progression and immunity

Campana, Lara; Bosurgi, Lidia; Rovere‐Querini, Patrizia

doi:10.1016/j.coi.2008.04.012

Cited by 118 publications

(108 citation statements)

References 48 publications

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“…Despite its critical roles in nucleus, such as DNA repair, interaction with transcriptional factors like p53, p73 and Rb protein, the functions of extracellular HMGB1 receive a great deal of attention recently (Stros et al, 2002;Banerjee et al, 2003;Krynetski et al, 2003;Jiao et al, 2007). It is noteworthy that HMGB1protein released from cancer cells is a double-edged sword: it promotes tumor neoangiogenesis; it triggers protective anti-neoplastic T-cell responses (Campana et al, 2008). HMGB1 protein which is secreted by dying cancer cells interacts with TLR4 expressed by dendritic cells (DCs) and activates anti-tumor T-cell immunity (Apetoh et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

High Mobility Group Box 1 Protein Is Methylated and Transported to Cytoplasm in Clear Cell Renal Cell Carcinoma

Zhao²,

Ding³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background:The high mobility group box 1 (HMGB1) protein is a widespread nuclear protein present in most cell types. It typically locates in the nucleus and functions as a nuclear cofactor in transcription regulation. However, HMGB1 can also localize in the cytoplasm and be released into extracellular matrix, where it plays critical roles in carcinogenesis and inflammation. However, it remains elusive whether HMGB1 is relocated to cytoplasm in clear cell renal cell carcinoma (ccRCC). Methods: Nuclear and cytoplasmic proteins were extracted by different protocols from 20 ccRCC samples and corresponding adjacent renal tissues. Western blotting and immunohistochemistry were used to identify the expression of HMGB1 in ccRCC. To elucidate the potential mechanism of HMGB1 cytoplasmic translocation, HMGB1 proteins were enriched by immunoprecipitation and analyzed by mass spectrometry (MS). Results: The HMGB1 protein was overexpressed and partially localized in cytoplasm in ccRCC samples (12/20, 60%, p<0.05). Immunohistochemistry results indicated that ccRCC of high nuclear grade possess more HMGB1 relocation than those with low grade (p<0.05). Methylation of HMGB1 at lysine 112 in ccRCC was detected by MS. Bioinformatics analysis showed that post-translational modification might affect the binding ability to DNA and mediate its translocation. Conclusion: Relocation of HMGB1 to cytoplasm was confirmed in ccRCC. Methylation of HMGB1 at lysine 112 might the redistribution of this cofactor protein.

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Section: Discussionmentioning

confidence: 99%

High Mobility Group Box 1 Protein Is Methylated and Transported to Cytoplasm in Clear Cell Renal Cell Carcinoma

Zhao²,

Ding³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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“…It is possible that this acute release of HMGB1 (as opposed to the chronic release typically seen in the tumor environment) might be mediating a more beneficial response. 33 For example, HMGB1 induced autophagy has been shown to sensitize cells to apoptosis in some situations. 34 It is also possible that secondary factors released into the media, such as virally encoded proteins, or even viral DNA may be mediating increased sensitivity in combination with HMGB1 (HMGB1 and microbial DNA can interact to activate TLR9 signaling).…”

Section: Discussionmentioning

confidence: 99%

Synergistic anti-tumor effects between oncolytic vaccinia virus and paclitaxel are mediated by the IFN response and HMGB1

Huang

Sikorski

Kirn³

et al. 2010

Gene Ther

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Recent developments in the field of oncolytic or tumor-selective viruses have meant that the clinical applications of these agents are now being considered in more detail. Like most cancer therapies it is likely that they will be used primarily in combination with other therapeutics. Although several reports have shown that oncolytic viruses can synergize with chemotherapies within an infected cancer cell, it would be particularly important to determine whether factors released from infected cells could enhance the action of chemotherapies at a distance. Here, we demonstrate in vitro synergy between oncolytic vaccinia and taxanes. However, we also show, for the first time, that this synergy is at least partly due to the release of factors from the infected cells that are capable of sensitizing surrounding cells to chemotherapy. Several cellular factors were identified as being mediators of this bystander effect, including type I interferon released soon after infection and high-mobility group protein B1 (HMGB1) released after cell death. This represents the first description of these mechanisms for beneficial interactions between viral and traditional tumor therapies. These data may provide a direct basis for the design of clinical trials with agents currently in the clinic, as well as providing insight into the development of next generation viral vectors.

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“…9 In the tumor microenvironment, HMGB1 recognition has a paradoxical effects on tumor immunity: it promotes tumor neoangiogenesis, but also triggers a protective antineoplastic T-cell response. 10 Moreover, receptor for advanced glycation end products and HMGB1 sustain autophagy and limits apoptosis, promoting pancreatic and colon tumor cell survival. [11][12][13] We have previously demonstrated that endogenous HMGB1 is a negative regulator of apoptosis in leukemia cells.…”

Section: Introductionmentioning

confidence: 99%

HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells

et al. 2010

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Autophagy, a tightly regulated lysosome-dependent catabolic pathway, is important in the regulation of cancer development and progression and in determining the response of tumor cells to anticancer therapy. However, the role of autophagy in leukemia still remains largely unknown. Here we show that high-mobility group box 1 (HMGB1), the best characterized damage-associated molecular pattern, was released from leukemia cell lines after chemotherapy-induced cytotoxicity and activated autophagy to protect against injury. Treatment with HMGB1-neutralizing antibodies increased the sensitivity of leukemia cells to chemotherapy; whereas, exogenous HMGB1 rendered these cells more resistant to drug-induced cytotoxicity. Moreover, exogenous HMGB1 increased autophagy as evaluated by increased expression of the autophagic marker microtubule-associated protein light chain 3-II, degradation of sequestosome 1 (p62) and autophagosome formation. Furthermore, knockdown or pharmacological inhibition of either phosphoinositide 3-kinase-III or extracellular signal-regulated kinase kinase mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase inhibited HMGB1-induced autophagy. Taken together, these results suggest that HMGB1 release after chemotherapy is a critical regulator of autophagy and a potential drug target for therapeutic interventions in leukemia.

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HMGB1: a two-headed signal regulating tumor progression and immunity

Cited by 118 publications

References 48 publications

High Mobility Group Box 1 Protein Is Methylated and Transported to Cytoplasm in Clear Cell Renal Cell Carcinoma

High Mobility Group Box 1 Protein Is Methylated and Transported to Cytoplasm in Clear Cell Renal Cell Carcinoma

Synergistic anti-tumor effects between oncolytic vaccinia virus and paclitaxel are mediated by the IFN response and HMGB1

HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells

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