High metallothionein predicts poor survival in glioblastoma multiforme

Mehrian‐Shai, Ruty; Yalon, Michal; Simon, Amos J.; Eyal, Eran; Pismenyuk, Tatyana; Moshe, Itai; Constantini, Shlomi; Toren, Amos

doi:10.1186/s12920-015-0137-6

Cited by 30 publications

(35 citation statements)

References 29 publications

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“…Deficiency in MT generally worsens the damage caused by neurotoxic factors or trauma (Giralt et al, 2002). However, in glioblastoma multiforme patients, high levels of MT are a negative prognostic factor, probably because MT make tumors more resistant to therapy (Mehrian-Shai et al, 2015).…”

Section: Metallothioneinsmentioning

confidence: 99%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

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Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem‐cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocyte‐specific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2‐ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.

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Section: Metallothioneinsmentioning

confidence: 99%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

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“…MT2A over-expression is associated with cell proliferation in cancerous breast tissue [ 90 ], with significantly modified breast cancer risk, and cell cycle is inhibited through silencing MT2A [ 91 ]. MT2A predicts high therapeutic value in hepatocellular carcinoma [ 92 ], whereas predicts poor survival in glioblastoma multiforme [ 93 ]. MT2A might be a chemosensitive indicator in gastric cancer (GC) [ 94 ], and another study found that MT2A might play a role in suppressing tumor activity through inhibiting NF-κB and might be a prognostic biomarker and potential target for individual therapy of GC [ 95 ] ( Table 1 ).…”

Section: Mt2a and Diseasementioning

confidence: 99%

Mammalian Metallothionein-2A and Oxidative Stress

Ling

Wei

Wang

et al. 2016

IJMS

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Mammalian metallothionein-2A (MT2A) has received considerable attention in recent years due to its crucial pathophysiological role in anti-oxidant, anti-apoptosis, detoxification and anti-inflammation. For many years, most studies evaluating the effects of MT2A have focused on reactive oxygen species (ROS), as second messengers that lead to oxidative stress injury of cells and tissues. Recent studies have highlighted that oxidative stress could activate mitogen-activated protein kinases (MAPKs), and MT2A, as a mediator of MAPKs, to regulate the pathogenesis of various diseases. However, the molecule mechanism of MT2A remains elusive. A deeper understanding of the functional, biochemical and molecular characteristics of MT2A would be identified, in order to bring new opportunities for oxidative stress therapy.

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“…The cytoprotective effect of MT3 in glioma cells has been reported by others. For instance, elevated MT3 expression in U87-MG glioblastoma cells than in normal astrocytes and other glioma cell line was correlated with an inactive conformational change of p53, resulting in attenuated apoptosis 17 . Hence, MT3 may contribute to glioma survival through diverse ways including increases in autophagy flux through lysosomal acidification.…”

Section: Discussionmentioning

confidence: 98%

“…As for glioma, induced expression of MT3 as well as MT1 and MT2 following arsenic trioxide treatment on U87-MG glioblastoma cells was demonstrated 16 , which may be postulated as a potential mechanism for glioma resistance. Importantly, Mehrian-Shai et al 17 recently reported that, in glioblastoma patients, high expression of including MT3 was associated with poor patient survival whereas low MT levels corresponded to good prognosis, suggesting the prognostic implications of Mts in glioma.…”

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confidence: 99%

A role of metallothionein-3 in radiation-induced autophagy in glioma cells

Cho

Lee

et al. 2020

Sci Rep

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Although metallothionein-3 (MT3), a brain-enriched form of metallothioneins, has been linked to Alzheimer's disease, little is known regarding the role of MT3 in glioma. As MT3 plays a role in autophagy in astrocytes, here, we investigated its role in irradiated glioma cells. Irradiation increased autophagy flux in GL261 glioma cells as evidenced by increased levels of LC3-II but decreased levels of p62 (SQSTM1). Indicating that autophagy plays a cytoprotective role in glioma cell survival following irradiation, measures inhibiting autophagy flux at various steps decreased their clonogenic survival of irradiated GL261 as well as SF295 and U251 glioma cells. Knockdown of MT3 with siRNA in irradiated glioma cells induced arrested autophagy, and decreased cell survival. At the same time, the accumulation of labile zinc in lysosomes was markedly attenuated by MT3 knockdown. Indicating that such zinc accumulation was important in autophagy flux, chelation of zinc with tetrakis-(2pyridylmethyl)ethylenediamine (TPEN), induced arrested autophagy in and reduced survival of GL261 cells following irradiation. Suggesting a possible mechanism for arrested autophagy, MT3 knockdown and zinc chelation were found to impair lysosomal acidification. Since autophagy flux plays a cytoprotective role in irradiated glioma cells, present results suggest that MT3 and zinc may be regarded as possible therapeutic targets to sensitize glioma cells to ionizing radiation therapy. Patients with glioblastoma, the most malignant form of glioma, usually succumb within a few years after the diagnosis despite aggressive chemo and radiotherapies following surgery 1. Such disheartening therapeutic outcomes desperately call for more effective measures. However, untoward biological characteristics of glioma such as aggressive local invasion and resistance to anticancer therapy, present a daunting obstacle in achieving this goal. Dysregulation of autophagy has been implicated in cancer cell proliferation, invasion, high histological grades, and poor prognosis in a wide spectrum of cancers. These findings highlight the possibility that autophagy-related molecules may prove useful as prognostic markers and/or therapeutic targets. In addition, many of anticancer drugs along with ionizing radiation (IR) are known to activate autophagy in cancer cells. The functional significance of autophagy activation associated with cancer therapeutics is still controversial. A growing body of evidence supports the possibility that autophagy plays a self-defensive cytoprotective role against toxicity induced by anti-cancer therapies 2-4 , although opposing data favoring the cytotoxic effect of autophagy are also available 2,3. Despite these controversies, the current consensus is that the modulation of autophagy may have significant effects in anti-cancer therapeutics. Although a number of intrinsic or extrinsic pathways of autophagy have been delineated, the final destination of all these pathways is the lysosome, where degradation of cargo contents occurs. For this reas...

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High metallothionein predicts poor survival in glioblastoma multiforme

Cited by 30 publications

References 29 publications

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Mammalian Metallothionein-2A and Oxidative Stress

A role of metallothionein-3 in radiation-induced autophagy in glioma cells

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