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1.  Direct molecular interactions between HMGB1 and TP53 in colorectal cancer 
Autophagy  2012;8(5):846-848.
Tumorigenesis and the efficacy of cancer therapeutics are both defined by the balance between autophagy and apoptosis. High-mobility group box 1 (HMGB1) is a DNA chaperone and extracellular damage-associated molecular pattern molecule (DAMP) with pro-autophagic activity. TP53/p53 plays a transcription-dependent and -independent role in the regulation of apoptosis, autophagy, metabolism, cell cycle progression, and many other processes. Both HMGB1 and TP53 are tightly linked with the development of cancer, associated with many of the hallmarks defining the altered biology of cancer. We have demonstrated that TP53-HMGB1 complexes regulate the balance between apoptosis and autophagy through regulation of the cytosolic localization of the reciprocal binding partner, whereby increased cytosolic HMGB1 enhances autophagy and increased cytosolic TP53 enhances apoptosis in colon cancer cells. We found that HMGB1-mediated autophagy promotes cell survival in TP53-dependent processes, and that TP53 inhibits autophagy through negative regulation of HMGB1-BECN1 complexes. Nuclear localization of TP53 and HMGB1 in tumors from patients with colon adenocarcinoma had a positive trend with survival time from diagnosis. Thus, HMGB1 and TP53 are critical in the crossregulation of apoptosis and autophagy and central to colon cancer biology.
doi:10.4161/auto.19891
PMCID: PMC3378423  PMID: 22647615
Apoptosis; autophagy; colorectal cancer; HMGB1; TP53
2.  p53/HMGB1 Complexes Regulate Autophagy and Apoptosis 
Cancer research  2012;72(8):1996-2005.
The balance between apoptosis (“programmed cell death”) and autophagy (“programmed cell survival”) is important in tumor development and response to therapy. Here we show that HMGB1 and p53 form a complex which regulates the balance between tumor cell death and survival. We demonstrate that knockout of p53 inHCT116 cells increases expression of cytosolic HMGB1 and induces autophagy. Conversely, knockout of HMGB1 in mouse embryonic fibroblasts increases p53 cytosolic localization and decreases autophagy. p53 is thus a negative regulator of the HMGB1/Beclin 1 complex, and HMGB1 promotes autophagy in the setting of diminished p53. HMGB1-mediated autophagy promotes tumor cell survival in the setting of p53-dependent processes. The HMGB1/p53 complex affects the cytoplasmic localization of the reciprocal binding partner thereby regulating subsequent levels of autophagy and apoptosis. These insights provide a novel link between HMGB1 and p53 in the crossregulation of apoptosis and autophagy in the setting of cell stress, providing insights into their reciprocal roles in carcinogenesis.
doi:10.1158/0008-5472.CAN-11-2291
PMCID: PMC3417120  PMID: 22345153
HMGB1; p53; Autophagy; Apoptosis; Colorectal cancer
3.  Inhibiting autophagy potentiates the anticancer activity of IFN1@/IFNα in chronic myeloid leukemia cells 
Autophagy  2013;9(3):317-327.
IFN1@ (interferon, type 1, cluster, also called IFNα) has been extensively studied as a treatment for patients with chronic myeloid leukemia (CML). The mechanism of anticancer activity of IFN1@ is complex and not well understood. Here, we demonstrate that autophagy, a mechanism of cellular homeostasis for the removal of dysfunctional organelles and proteins, regulates IFN1@-mediated cell death. IFN1@ activated the cellular autophagic machinery in immortalized or primary CML cells. Activation of JAK1-STAT1 and RELA signaling were required for IFN1@-induced expression of BECN1, a key regulator of autophagy. Moreover, pharmacological and genetic inhibition of autophagy enhanced IFN1@-induced apoptosis by activation of the CASP8-BID pathway. Taken together, these findings provide evidence for an important mechanism that links autophagy to immunotherapy in leukemia.
doi:10.4161/auto.22923
PMCID: PMC3590253  PMID: 23242206
IFN1@; autophagy; apoptosis; immunotherapy; chronic myeloid leukemia
4.  The Receptor for Advanced Glycation End-Products (RAGE) Protects Pancreatic Tumor Cells Against Oxidative Injury 
Antioxidants & Redox Signaling  2011;15(8):2175-2184.
Abstract
Reactive oxygen species, including hydrogen peroxide (H2O2), can cause toxicity and act as signaling molecules in various pathways regulating both cell survival and cell death. However, the sequence of events between the oxidative insult and cell damage remains unclear. In the current study, we investigated the effect of oxidative stress on activation of the Receptor for Advanced Glycation End-products (RAGE) and subsequent protection against H2O2-induced pancreatic tumor cell damage. We found that exposure of pancreatic tumor cells to H2O2 provoked a nuclear factor kappa B (NF-κB)-dependent increase in RAGE expression. Further, suppression of RAGE expression by RNA interference increased the sensitivity of pancreatic tumor cells to oxidative injury. Furthermore, targeted knockdown of RAGE led to increased cell death by apoptosis and diminished cell survival by autophagy during H2O2-induced oxidative injury. Moreover, we demonstrate that RAGE is a positive feedback regulator for NF-κB as knockdown of RAGE decreased H2O2-induced activity of NF-κB. Taken together, these results suggest that RAGE is an important regulator of oxidative injury. Antioxid. Redox Signal. 15, 2175–2184.
doi:10.1089/ars.2010.3378
PMCID: PMC3166176  PMID: 21126167
5.  High Mobility Group Box 1 (HMGB1) Activates an Autophagic Response to Oxidative Stress 
Antioxidants & Redox Signaling  2011;15(8):2185-2195.
Abstract
Aims
Autophagy, the process by which cells break down spent biochemical and damaged components, plays an important role in cell survival following stress. High mobility group box 1 (HMGB1) regulates autophagy in response to oxidative stress.
Results
Exogenous hydrogen peroxide (H2O2) treatment or knockdown of the major superoxide scavenger enzyme, superoxide dismutase 1 (SOD1), by small interfering RNA (siRNA) increases autophagy in mouse and human cell lines. Addition of either SOD1 siRNA or H2O2 promotes cytosolic HMGB1 expression and extracellular release. Importantly, inhibition of HMGB1 release or loss of HMGB1 decreases the number of autophagolysosomes and autophagic flux under oxidative stress in vivo and in vitro.
Innovation:
HMGB1 release may be a common mediator of response to oxidative stress.
Conclusion
HMGB1 is important for oxidative stress-mediated autophagy and serves as a new target for the treatment of stress-associated disorders. Antioxid. Redox Signal. 15, 2185–2195.
doi:10.1089/ars.2010.3666
PMCID: PMC3166205  PMID: 21395369
6.  The Receptor for Advanced Glycation End-products (RAGE) Sustains Autophagy and Limits Apoptosis, Promoting Pancreatic Tumor Cell Survival 
Cell death and differentiation  2009;17(4):666-676.
Activation of the induced receptor for advanced glycation endproducts (RAGE) leads to initiation of NF-κB and MAP kinase signaling pathways resulting in propagation and perpetuation of inflammation. RAGE knock out animals are less susceptible to acute inflammation and carcinogen induced tumor development. We have reported that most forms of tumor cell death result in release of the RAGE ligand, HMGB1. We now report a novel role for RAGE in the tumor cell response to stress. Targeted knockdown of RAGE in the tumor cell, leads to increased apoptosis, diminished autophagy and decreased tumor cell survival . In contrast, overexpression of RAGE is associated with enhanced autophagy, diminished apoptosis and greater tumor cell viability. RAGE limits apoptosis through a p53 dependent mitochondrial pathway. Moreover, RAGE-sustained autophagy is associated with decreased phosphorylation of mTOR and increased Beclin-1/VPS34 autophagosome formation. These findings demonstrate that the inflammatory receptor RAGE plays a heretofore unrecognized role in the tumor cell response to stress. Furthermore, these studies establish a direct link between inflammatory mediators in the tumor microenvironment and resistance to programmed cell death. Our data suggest that targeted inhibition of RAGE or its ligands may serve as novel targets to enhance current cancer therapies.
doi:10.1038/cdd.2009.149
PMCID: PMC3417122  PMID: 19834494
7.  HMGB1 [High Mobility Group Box 1] is Essential for Mitochondrial Quality Control 
Cell Metabolism  2011;13(6):701-711.
Mitochondria are organelles centrally important for bioenergetics as well as regulation of apoptotic death in eukaryotic cells. High mobility group box 1 (HMGB1), an evolutionarily conserved chromatin-associated protein which maintains nuclear homeostasis, is also a critical regulator of mitochondrial function and morphology. We show that heat shock protein beta-1 (HSPB1/ HSP27) is the downstream mediator of this effect. Disruption of the HSPB1 gene in embryonic fibroblasts with wild-type HMGB1 recapitulates the mitochondrial fragmentation, deficits in mitochondrial respiration, and adenosine triphosphate (ATP) synthesis observed with targeted deletion of HMGB1. Forced expression of HSPB1 reverses this phenotype in HMGB1 knockout cells. Mitochondrial effects mediated by HMGB1 regulation of HSPB1 expression, serves as a defense against mitochondrial abnormality, enabling clearance and autophagy in the setting of cellular stress. Our findings reveal a novel role for HMGB1 in autophagic surveillance with important effects on mitochondrial quality control.
doi:10.1016/j.cmet.2011.04.008
PMCID: PMC3293110  PMID: 21641551
8.  HMGB1 is a therapeutic target for leukemia 
High mobility group box 1 (HMGB1) is a nuclear DNA-binding protein, which functions as Damage Associated Molecular Pattern molecule (DAMP) when released from cells under conditions of stress, such as injury and infection. Recent studies indicate that HMGB1 plays an important role in leukemia pathogenesis and chemotherapy resistance. Serum HMGB1 is increased in childhood acute lymphocytic leukemia as compared to healthy control and complete remission groups. Moreover, HMGB1 is a negative regulator of apoptosis in leukemia cells through regulation of Bcl-2 expression and caspase-3 activity. As a positive regulator of autophagy, intracellular HMGB1 interacts with Beclin 1 in leukemia cells leading to autophagosome formation. Additionally, exogenous HMGB1 directly induces autophagy and cell survival in leukemia cells. Experimental strategies that selectively target HMGB1 effectively reverse and prevent chemotherapy resistance in leukemia cells, suggesting that HMGB1 is a novel therapeutic target in leukemia.
PMCID: PMC3301433  PMID: 22432086
HMGB1; leukemia; apoptosis; autophagy; chemotherapy
9.  A critical role for UVRAG in apoptosis 
Autophagy  2011;7(10):1242-1244.
Autophagy and apoptosis are tightly regulated biological processes that are crucial for cell growth, development and tissue homeostasis. UVRAG (UV radiation resistance-associated gene), a mammalian homolog of yeast Vps38, activates the Beclin 1/PtdIns3KC3 (class III phosphatidylinositol-3-kinase) complex, which promotes autophagosome formation. Moreover, UVRAG promotes autophagosome maturation by recruiting class C Vps complexes (HOPS complexes) and Rab7 of the late endosome. We found that UVRAG has anti-apoptotic activity during tumor therapy through interactions with Bax. UVRAG inhibits Bax translocation from the cytosol to mitochondria during chemotherapy- or UV irradiation-induced apoptosis of human tumor cells. Moreover, deletion of the UVRAG C2 domain abolishes Bax binding and anti-apoptotic activity. These results suggest that, in addition to its previously recognized pro-autophagy activity in response to starvation, UVRAG has cytoprotective functions in the cytosol that control the localization of Bax in tumor cells exposed to apoptotic stimuli.
doi:10.4161/auto.7.10.16507
PMCID: PMC3210309  PMID: 21606679
UVRAG; Bax; apoptosis; autophagy; mitochondria; tumor therapy
10.  Autophagy regulates myeloid cell differentiation by p62/SQSTM1-mediated degradation of PML-RARα oncoprotein 
Autophagy  2011;7(4):401-411.
PML-RARα oncoprotein is a fusion protein of promyelocytic leukemia (PML) and the retinoic acid receptor-α (RARα) and causes acute promyelocytic leukemias (APL). A hallmark of all-trans retinoic acid (ATRA) responses in APL is PML-RARα degradation, which promotes cell differentiation. Here, we demonstrated that autophagy is a crucial regulator of PML-RARα degradation. Inhibition of autophagy by short hairpin (sh) RNA that target essential autophagy genes such as ATG1, ATG5 and PI3KC3, and by autophagy inhibitors (e.g., 3-methyladenine), blocked PML-RARα degradation and subsequently granulocytic differentiation of human myeloid leukemic cells. In contrast, rapamycin, the mTOR kinase inhibitor, enhanced autophagy and promoted ATRA-induced PML-RARα degradation and myeloid cell differentiation. Moreover, PML-RARα co-immunoprecipitated with the ubiquitin-binding adaptor protein p62/SQSTM1, which is degraded through autophagy. Furthermore, knockdown of p62/SQSTM1 inhibited ATRA-induced PML-RARα degradation and myeloid cell differentiation. The identification of PML-RARα as a target of autophagy provides new insight into the mechanism of action of ATRA and its specificity for APL.
doi:10.4161/auto.7.4.14397
PMCID: PMC3127220  PMID: 21187718
autophagy; differentiation; oncoprotein; leukemia; degradation; PML-RARa; p62/SQSTM1
11.  HMGB1 Release and Redox Regulates Autophagy and Apoptosis in Cancer Cells 
Oncogene  2010;29(38):5299-5310.
The functional relationship and cross-regulation between autophagy and apoptosis is complex. Here we show that high-mobility group box 1 protein (HMGB1) is a redox-sensitive regulator of the balance between autophagy and apoptosis. In cancer cells, anti-cancer agents enhanced autophagy and apoptosis as well as HMGB1 release. HMGB1 release may be a pro-survival signal for residual cells following various cytotoxic cancer treatments. Diminished HMGB1 by shRNA transfection or inhibition of HMGB1 release by ethyl pyruvate or other small molecules led to predominantly apoptosis and decreased autophagy in stressed cancer cells. In this setting, reducible HMGB1 binds to the receptor for advanced glycation end products (RAGE) but not Toll-like receptor 4 (TLR4), 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). Oxidized HMGB1 conversely 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 link autophagy and apoptosis, representing a suitable target when coupled with conventional tumor treatments.
doi:10.1038/onc.2010.261
PMCID: PMC2945431  PMID: 20622903
12.  Endogenous HMGB1 regulates autophagy 
The Journal of Cell Biology  2010;190(5):881-892.
HMGB1 displaces Bcl-2 from Beclin1 to induce and sustain autophagy in response to cell stress.
Autophagy clears long-lived proteins and dysfunctional organelles and generates substrates for adenosine triphosphate production during periods of starvation and other types of cellular stress. Here we show that high mobility group box 1 (HMGB1), a chromatin-associated nuclear protein and extracellular damage-associated molecular pattern molecule, is a critical regulator of autophagy. Stimuli that enhance reactive oxygen species promote cytosolic translocation of HMGB1 and thereby enhance autophagic flux. HMGB1 directly interacts with the autophagy protein Beclin1 displacing Bcl-2. Mutation of cysteine 106 (C106), but not the vicinal C23 and C45, of HMGB1 promotes cytosolic localization and sustained autophagy. Pharmacological inhibition of HMGB1 cytoplasmic translocation by agents such as ethyl pyruvate limits starvation-induced autophagy. Moreover, the intramolecular disulfide bridge (C23/45) of HMGB1 is required for binding to Beclin1 and sustaining autophagy. Thus, endogenous HMGB1 is a critical pro-autophagic protein that enhances cell survival and limits programmed apoptotic cell death.
doi:10.1083/jcb.200911078
PMCID: PMC2935581  PMID: 20819940
13.  DAMP-mediated autophagy contributes to drug resistance 
Autophagy  2011;7(1):112-114.
Damage-associated molecular pattern molecules (DAMPs) are cellularly derived molecules that can initiate and perpetuate immune responses following trauma, ischemia and other types of tissue damage in the absence of pathogenic infection. High mobility group box 1 (HMGB1) is a prototypical DAMP and is associated with the hallmarks of cancer. Recently we found that HMGB1 release after chemotherapy treatment is a critical regulator of autophagy and a potential drug target for therapeutic interventions in leukemia. Overexpression of HMGB1 by gene transfection rendered leukemia cells resistant to cell death; whereas depletion or inhibition of HMGB1 and autophagy by RNA interference or pharmacological inhibitors increased the sensitivity of leukemia cells to chemotherapeutic drugs. HMGB1 release sustains autophagy as assessed by microtubule-associated protein 1 light chain 3 (LC3) lipidation, redistribution of LC3 into cytoplasmic puncta, degradation of p62 and accumulation of autophagosomes and autolysosomes. Moreover, these data suggest a role for HMGB1 in the regulation of autophagy through the PI3KC3-MEKERK pathway, supporting the notion that HMGB1-induced autophagy promotes tumor resistance to chemotherapy.
doi:10.4161/auto.7.1.14005
PMCID: PMC3039734  PMID: 21068541
DAMP; autophagy; HMGB1; chemotherapy resistance; leukemia; PI3KC3; ERK

Results 1-13 (13)