Molecular mechanisms of necrosis in glioblastoma: The role of glutamate excitotoxicity

Noch, Evan; Khalili, Kamel

doi:10.4161/cbt.8.19.9762

Cited by 125 publications

(104 citation statements)

References 67 publications

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“…Necrosis is a hallmark feature of glioblastoma (79) and has been shown to occur through a number of mechanisms (reviewed in ref. 80). One mechanism of necrosis in glioma has been suggested to involve the accumulation of the neurotransmitter, glutamate, in the extracellular space in the brain (81).…”

Section: Acmsd Dysregulation In Tumor Cells: a Speculative Role For Bmentioning

confidence: 99%

The Kynurenine Pathway in Brain Tumor Pathogenesis

et al. 2012

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Brain tumors are among the most common and most chemoresistant tumors. Despite treatment with aggressive treatment strategies, the prognosis for patients harboring malignant gliomas remains dismal. The kynurenine pathway (KP) is the principal route of L-tryptophan catabolism leading to the formation of the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD þ ), and important neuroactive metabolites, including the neurotoxin, quinolinic acid (QUIN), the neuroprotective agent, picolinic acid (PIC), the T H 17/Treg balance modulator, 3-hydroxyanthranilic acid (3-HAA), and the immunosuppressive agent, L-Kynurenine (KYN). This review provides a new perspective on KP dysregulation in defeating antitumor immune responses, specifically bringing light to the lower segment of the KP, particularly QUIN-induced neurotoxicity and downregulation of the enzyme a-amino-b-carboxymuconate-e-semialdehyde decarboxylase (ACMSD) as a potential mechanism of tumor progression. Given its immunosuppressive effects, 3-HAA produced from the KP may also play a role in suppressing antitumor immunity in human tumors. The enzyme indoleamine 2, 3-dioxygenase (IDO-1) initiates and regulates the first step of the KP in most cells. Mounting evidence directly implicates that the induction and overexpression of IDO-1 in various tumors is a crucial mechanism facilitating tumor immune evasion and persistence. Tryptophan 2, 3-dioxygenase (TDO-2), which initiates the same first step of the KP as IDO-1, has likewise recently been shown to be a mechanism of tumoral immune resistance. Further, it was also recently shown that TDO-2-dependent production of KYN by brain tumors might be a novel mechanism for suppressing antitumor immunity and supporting tumor growth through the activation of the Aryl hydrocarbon receptor (AhR). This newly identified TDO-2-KYN-AhR signaling pathway opens up exciting future research opportunities and may represent a novel therapeutic target in cancer therapy. Our discussion points to a number of KP components, namely TDO-2, IDO-1, and ACMSD, as important therapeutic targets for the treatment of brain cancer. Targeting the KP in brain tumors may represent a viable strategy likely to prevent QUIN-induced neurotoxicity and KYN and 3-HAA-mediated immune suppression. Cancer Res; 72(22); 5649-57. Ó2012 AACR.

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Section: Acmsd Dysregulation In Tumor Cells: a Speculative Role For Bmentioning

confidence: 99%

The Kynurenine Pathway in Brain Tumor Pathogenesis

et al. 2012

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“…Functionally, it is accompanied by ATP depletion, HMGB1 release, and failure of the plasma membrane ionic pumps. Necrosis is a common feature of human cancers and often related to poor prognosis, especially in glioblastoma (46), but how necrosis arises in human cancers is not understood. We speculate on this subject as follows: Given that c-MYC stimulates energyconsuming processes, rapid depletion of ATP levels resulting from activation of c-MYC under dual-deprivation conditions might drive the cancer cells to necrosis.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of c-MYC Protein Levels Contributes to Cancer Cell Survival under Dual Deficiency of Oxygen and Glucose

et al. 2010

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The c-MYC protein participates in energy-consuming processes such as proliferation and ribosome biosynthesis, and its expression is often dysregulated in human cancers. Cancer cells distant from blood vessels in solid tumors are in short supply of oxygen and nutrition yet can adapt to the microenvironment and survive under metabolic stress. The role and regulation of c-MYC protein in the tumor microenvironment of limited energy sources are poorly understood. Here, we show that c-MYC protein levels in cancer cells are strikingly reduced in the area distant from the blood vessels in vivo and also under oxygen-and glucosedeprived conditions in vitro. The rapid reduction of c-MYC protein levels requires low levels of both oxygen and glucose, and under these conditions, downregulation is mainly achieved by enhanced degradation. Suppression of c-MYC protein levels by small hairpin RNA decreases the necrotic cell death induced by oxygen and glucose deprivation. Thus, the environmental milieu regulates c-MYC protein levels, and downregulation of c-MYC might be a strategy for cancer cells to survive under conditions of limited energy sources. Cancer Res; 70(24); 10213-23. Ó2010 AACR.

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“…For experiments using no serum or glucose, DMEM lacking only serum or lacking both serum and glucose in glioblastoma, a process which itself may induce necrosis. 24 Therefore, this molecule holds much potential impact as a novel target for the treatment of glioblastoma. By better understanding the mechanism of AEG-1 induction by hypoxia and glucose deprivation and the biological significance of this AEG-1 upregulation, it may be possible to conduct high-throughput chemical screens for small molecule inhibitors of the AEG-1 pathway to improve the overall prognosis of patients diagnosed with glioblastoma.…”

confidence: 99%