Proteasome inhibition protects HT22 neuronal cells from oxidative glutamate toxicity

Leyen, Klaus van; Siddiq, Ambreena; Ratan, Rajiv R.; Lo, Eng H.

doi:10.1111/j.1471-4159.2004.02915.x

Cited by 60 publications

(65 citation statements)

References 33 publications

(75 reference statements)

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“…These results are consistent with previous observations in other cell types, indirectly suggesting that disruption of redox homeostasis could be important in determining proteasome inhibitor effectiveness (Emanuele et al, 2002;Ling et al, 2003;Fribley et al, 2004;van Leyen et al, 2005;Pei et al, 2004;Minami et al, 2005). This effect might be related at least in part to the cell types analysed, as in other studies, antioxidants have been shown not to protect from bortezomib-mediated cell death, while ascorbic acid protection was due to direct binding to bortezomib (Zou et al, 2006).…”

Section: Discussionsupporting

confidence: 92%

Redox homeostasis modulates the sensitivity of myeloma cells to bortezomib

Nerini-Molteni¹,

Ferrarini

Cozza³

et al. 2008

Br J Haematol

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SummaryThe use of proteasome inhibitors have been a major advance in the treatment of multiple myeloma (MM), but their mechanisms of action remain largely unclear. A better understanding of the cellular events downstream of proteasome inhibition is essential to improve the response and identify new combination therapies for MM and other malignancies. This study analysed the relationships between redox homeostasis and bortezomib treatment in MM cells. Our data showed that decreasing intracellular glutathione through buthionine sulfoximine treatment strongly enhances bortezomib toxicity, whilst antioxidants protect MM cells from bortezomib-mediated cell death. Bortezomib treatment decreases intracellular glutathione both in MM cell lines and in malignant plasma cells obtained from MM patients. Glutamatecysteine ligase (GCLM) and haem-oxygenase-1 (HMOX1), two genes involved in the Nrf-2-mediated antioxidant response, as well as two eIF2a-downstream transcription factors, activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), are upregulated, indicating that redox-related adaptive responses are initiated in bortezomib-treated MM cells. These findings demonstrate tight links between sensitivity to proteasome inhibition and redox homeostasis in MM cells and have potential implications for treatment.

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Section: Discussionsupporting

confidence: 92%

Redox homeostasis modulates the sensitivity of myeloma cells to bortezomib

Nerini-Molteni¹,

Ferrarini

Cozza³

et al. 2008

Br J Haematol

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“…This provides an explanation of how tBHQ restrains AIF-mediated apoptosis under glutamate toxicity. Consistent with previous reports, no significant activation of caspase-3/7 was observed during glutamate-induced oxidative toxicity (Tan et al, 1998;van Leyen et al, 2005;Zhang and Bhavnani, 2006). Caspase activation during the initiation of apoptosis requires ATP (Li et al, 1997a;Hu et al, 1999;Fukui et al, 2009 reported that the lack of caspase-3/7 activation may result from rapid onset of mitochondrial dysfunction and energy depletion induced by glutamate.…”

Section: Discussionsupporting

confidence: 80%

Sequential Upregulation of Superoxide Dismutase 2 and Heme Oxygenase 1 by tert-Butylhydroquinone Protects Mitochondria during Oxidative Stress

2015

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Oxidative stress is linked to mitochondrial dysfunction in aging and neurodegenerative conditions. The transcription factor nuclear factor E2-related factor 2 (Nrf2)-antioxidant response element (ARE) regulates intracellular antioxidative capacity to combat oxidative stress. We examined the effect of tertbutylhydroquinone (tBHQ), an Nrf2-ARE signaling pathway inducer, on mitochondrial function during oxidative challenge in neurons. tBHQ prevented glutamate-induced cytotoxicity in an HT-22 neuronal cell line even with an 8-hour exposure delay. tBHQ blocked glutamate-induced intracellular reactive oxygen species (ROS) and mitochondrial superoxide accumulation. It also protected mitochondrial function under glutamate toxicity, including maintaining mitochondrial membrane potential, mitochondrial Ca 21 hemostasis, and mitochondrial respiration. Glutamate-activated, mitochondria-mediated apoptosis was inhibited by tBHQ as well. In rat primary cortical neurons, tBHQ protected cells from both glutamate and buthionine sulfoximine toxicity. We found that tBHQ scavenged ROS and induced a rapid upregulation of superoxide dismutase 2 (SOD2) expression and a delayed upregulation of heme oxygenase 1 (HO-1) expression. In HT-22 cells with a knockdown of SOD2 expression, delayed treatment with tBHQ failed to prevent glutamate-induced cell death. Briefly, tBHQ rescues mitochondrial function by sequentially increasing SOD2 and HO-1 expression during glutamate-mediated oxidative stress. This study is the first to demonstrate the role of tBHQ in preserving mitochondrial function during oxidative challenge and provides a clinically relevant argument for using tBHQ against acute neuron-compromising conditions.

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“…This neural cell line was chosen because HT-22 cells are a well-characterized model of neural oxidative injury (30,46). These cells undergo oxidative stress-induced toxicity upon exposure to glutamate, which blocks glutamate-cystine antiporters in the plasma membrane, resulting in GSH deficiency and oxidative cell death (46). HT-22 cells were maintained in DMEM with glutamine, supplemented with 10% fetal bovine serum and penicillin=streptomycin (0.2%).…”

Section: Protein Extract Preparationmentioning

confidence: 99%

C-Terminus of Heat Shock Cognate 70 Interacting Protein Increases Following Stroke and Impairs Survival Against Acute Oxidative Stress

Stankowski

Zeiger

Cohen

et al. 2011

Antioxidants & Redox Signaling

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The decision to remove or refold oxidized, denatured, or misfolded proteins by heat shock protein 70 and its binding partners is critical to determine cell fate under pathophysiological conditions. Overexpression of the ubiquitin ligase C-terminus of HSC70 interacting protein (CHIP) can compensate for failure of other ubiquitin ligases and enhance protein turnover and survival under chronic neurological stress. The ability of CHIP to alter cell fate after acute neurological injury has not been assessed. Using postmortem human tissue samples, we provide the first evidence that cortical CHIP expression is increased after ischemic stroke. Oxygen glucose deprivation in vitro led to rapid protein oxidation, antioxidant depletion, proteasome dysfunction, and a significant increase in CHIP expression. To determine if CHIP upregulation enhances neural survival, we overexpressed CHIP in vitro and evaluated cell fate 24 h after acute oxidative stress. Surprisingly, CHIP overexpressing cells fared worse against oxidative injury, accumulated more ubiquitinated and oxidized proteins, and experienced decreased proteasome activity. Conversely, using small interfering RNA to decrease CHIP expression in primary neuronal cultures improved survival after oxidative stress, suggesting that increases in CHIP observed after stroke like injuries are likely correlated with diminished survival and may negatively impact the neuroprotective potential of heat shock protein 70.

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Proteasome inhibition protects HT22 neuronal cells from oxidative glutamate toxicity

Cited by 60 publications

References 33 publications

Redox homeostasis modulates the sensitivity of myeloma cells to bortezomib

Redox homeostasis modulates the sensitivity of myeloma cells to bortezomib

Sequential Upregulation of Superoxide Dismutase 2 and Heme Oxygenase 1 by tert-Butylhydroquinone Protects Mitochondria during Oxidative Stress

C-Terminus of Heat Shock Cognate 70 Interacting Protein Increases Following Stroke and Impairs Survival Against Acute Oxidative Stress

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