HMGB1 as an autocrine stimulus in human T98G glioblastoma cells: role in cell growth and migration

Bassi, Rajiv; Giussani, Paola; Anelli, Viviana; Colleoni, T.; Pedrazzi, Marco; Patrone, Mauro; Viani, Paola; Sparatore, Bianca; Melloni, Edon; Riboni, Laura

doi:10.1007/s11060-007-9488-y

Cited by 77 publications

(69 citation statements)

References 46 publications

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“…[42][43][44] It is well established that exogenous HMGB1 induces MEK-ERK activation in immune cells and cancer cells. 19,22,32,45 Here, we found that 3-MA inhibited HMGB1-induced phosphorylation of ERK, indicating that ERK is a downstream signal of PI3K. Importantly, knockdown or pharmacological inhibition of MEK-ERK attenuated HMGB1-induced LC3 conversion, suggesting that MEK-ERK is also required for HMGB1-induced autophagy in leukemia cells.…”

Section: Discussionmentioning

confidence: 75%

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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Section: Discussionmentioning

confidence: 75%

HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells

et al. 2010

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“…Furthermore, we show here that microglial cells receive signals from gliomas via TLRs. Gliomas can constitutively release heat-shock proteins, the high-mobility group box 1 protein, and hyluronan (23)(24)(25) and all these factors have been shown to stimulate TLRs (26). It is possible that these factors were present in our GCM, which was used to stimulate microglial MT1-MMP expression and activity in vitro.…”

Section: Glioma Cells Induce Microglial Mt1-mmp Expression Via Tlr Simentioning

confidence: 99%

Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

Marković

Vinnakota

Chirasani

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

346

328

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for highly malignant gliomas (World Health Organization grade III and IV) there is no successful treatment; patients have an average survival time of approximately 1 y after diagnosis. Glioma cells are highly invasive and infiltrate normal brain tissue, and as a result, surgical resection is always incomplete. Degradation of ECM by membrane-bound and secreted metalloproteases facilitates glioma invasion. In particular, the membrane-bound metalloproteases are pivotal for tumor invasion as they very efficiently digest extracellular matrix proteins and also activate secreted metalloproteases (1) like matrix metalloproteinase-2 (MMP-2, also known as gelatinase A), which is one of the major proteases involved in glioma invasion in mouse models (2) and probably also in humans (3). Hence, membrane-inserted metalloproteases like membrane type 1 matrix metalloproteinase (MT1-MMP) can enable gliomas to invade the brain parenchyma as single cells (4).Microglia are the intrinsic immune cells of the brain; they control the innate and the adaptive immune response in the CNS and are activated by inflammatory or other pathological stimuli (5). Activation of microglial toll-like receptors (TLRs) triggers the innate immune response and can initiate host-defense and tissue repair mechanisms, but also CNS inflammation, neurodegeneration, and trauma (5, 6). As microglial cells are attracted toward glioma in large numbers-glioma tissue consists of as much as 30% microglial cells-and because microglia density in gliomas positively correlates with malignancy, invasiveness, and grading of the tumors (7-9), we investigated if microglia may actively contribute to glioma expansion. Here, we show that soluble factors released from glioma stimulate microglial TLRs, resulting in microglial MT1-MMP expression via the TLR downstream signaling molecules MyD88 and p38 MAPK. In turn, MT1-MMP expression and activity in these immune cells promotes glioma cell invasion and tumor expansion. ResultsGlioma Associated Microglia Over-Express MT1-MMP. We analyzed the expression pattern of the matrix protease MT1-MMP in mouse and human gliomas and found the enzyme to be expressed predominantly in microglial cells closely associated with the tumors. Whereas tumor-free human brain samples showed virtually no MT1-MMP expression, we detected intense MT1-MMP labeling, especially in higher-grade gliomas. Importantly, in human samples, immunolabeling for the microglial marker Iba1 and for MT1-MMP largely overlapped [supporting information (SI) Fig. S1 A-D and Table S1]. Likewise, after injection of a human glioma cell line (U373 cells) into immunodeficient mice, we detected that microglia represent the predominant cell type contributing intratumoral MT1-MMP expression (see Fig. S1E).In our in vivo mouse model, the glioma cells were identified by stable expression of EGFP and microglial cells by immunolabeling for Iba1. In sections obtained from mice 2 weeks after intracerebral injection with isogenic glioma cells (GL261 cells), we found an increased density of mic...

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“…The wound area was observed by microscopy (Olympus CK2) (magnifications, ϫ100). Relative cell migration distance was determined by measuring the wound width and subtracting this from the initial value as previously described: cell migration distance ϭ initial wound width at day 0 Ϫ wound width at the day of measurement (Bassi et al, 2008). A total of three areas were randomly selected and examined in each well.…”

Section: Cell Migration Assaysmentioning

confidence: 99%

Lipocalin-2 Is an Autocrine Mediator of Reactive Astrocytosis

Lee¹,

Park²,

Lee³

et al. 2009

J. Neurosci.

239

238

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Astrocytes, the most abundant glial cell type in the brain, provide metabolic and trophic support to neurons and modulate synaptic activity. In response to a brain injury, astrocytes proliferate and become hypertrophic with an increased expression of intermediate filament proteins. This process is collectively referred to as reactive astrocytosis. Lipocalin 2 (lcn2) is a member of the lipocalin family that binds to small hydrophobic molecules. We propose that lcn2 is an autocrine mediator of reactive astrocytosis based on the multiple roles of lcn2 in the regulation of cell death, morphology, and migration of astrocytes. lcn2 expression and secretion increased after inflammatory stimulation in cultured astrocytes. Forced expression of lcn2 or treatment with LCN2 protein increased the sensitivity of astrocytes to cytotoxic stimuli. Iron and BIM (Bcl-2-interacting mediator of cell death) proteins were involved in the cytotoxic sensitization process. LCN2 protein induced upregulation of glial fibrillary acidic protein (GFAP), cell migration, and morphological changes similar to characteristic phenotypic changes termed reactive astrocytosis. The lcn2-induced phenotypic changes of astrocytes occurred through a Rho-ROCK (Rho kinase)-GFAP pathway, which was positively regulated by nitric oxide and cGMP. In zebrafishes, forced expression of rat lcn2 gene increased the number and thickness of cellular processes in GFAP-expressing radial glia cells, suggesting that lcn2 expression in glia cells plays an important role in vivo. Our results suggest that lcn2 acts in an autocrine manner to induce cell death sensitization and morphological changes in astrocytes under inflammatory conditions and that these phenotypic changes may be the basis of reactive astrocytosis in vivo.

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HMGB1 as an autocrine stimulus in human T98G glioblastoma cells: role in cell growth and migration

Cited by 77 publications

References 46 publications

HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells

HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells

Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

Lipocalin-2 Is an Autocrine Mediator of Reactive Astrocytosis

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