The oxido-metabolic driver ATF4 enhances temozolamide chemo-resistance in human gliomas

Chen, Daishi; Rauh, Manfred; Buchfelder, Michael; Eyüpoglu, Ilker Y.; Savaskan, Nicolai Ε.

doi:10.18632/oncotarget.17737

Cited by 62 publications

(50 citation statements)

References 35 publications

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“…Correspondingly, it has been shown that ATF4 and NRF2 inhibit ferroptosis at least partly through upregulating SLC7A11 expression, whereas p53 promotes ferroptosis by repressing SLC7A11 expression [ 51 – 55 ]. In addition, it has been shown that ATF4 and NRF2 promote resistance to various cellular stresses, including oxidative stress, genotoxic stress induced by chemotherapy, and proteasome inhibition, at least partly through SLC7A11 [ 26 , 31 , 56 , 57 ], which is in line with the similar protective functions of SLC7A11 in mediating these stress responses as discussed in the previous section. Recent studies have indicated that NRF2 and ATF4 regulate cancer cell dependency on either glucose or glutamine through SLC7A11.…”

Section: Molecular Regulation Of Slc7a11supporting

confidence: 55%

Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer

Koppula

Zhang

et al. 2018

Cancer Communications

530

413

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Cancer cells often upregulate nutrient transporters to fulfill their increased biosynthetic and bioenergetic needs, and to maintain redox homeostasis. One nutrient transporter frequently overexpressed in human cancers is the cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11; also known as xCT). SLC7A11 promotes cystine uptake and glutathione biosynthesis, resulting in protection from oxidative stress and ferroptotic cell death. Recent studies have unexpectedly revealed that SLC7A11 also plays critical roles in glutamine metabolism and regulates the glucose and glutamine dependency of cancer cells. This review discusses the roles of SLC7A11 in regulating the antioxidant response and nutrient dependency of cancer cells, explores our current understanding of SLC7A11 regulation in cancer metabolism, and highlights key open questions for future studies in this emerging research area. A deeper understanding of SLC7A11 in cancer metabolism may identify new therapeutic opportunities to target this important amino acid transporter for cancer treatment.

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Section: Molecular Regulation Of Slc7a11supporting

confidence: 55%

Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer

Koppula

Zhang

et al. 2018

Cancer Communications

530

413

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“…B, Cell viability was detected by CCK-8 assay. 32,33 The current study demonstrated that P2X4R knockdown reduced ATF4 expression dependent on BDNF/TrkB signaling and ATF4 overexpression reversed the effects of P2X4R on glioma cell growth and apoptosis. D, Cell death detection ELISA kit was used to detect cells apoptosis.…”

Section: Discussionmentioning

confidence: 54%

P2X4R silence suppresses glioma cell growth through BDNF/TrkB/ATF4 signaling pathway

Huo

Chen

2018

J of Cellular Biochemistry

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Purinergic receptor P2X 4 (P2X4R), a member of purinergic channels family and a subtype of ionotropic adenosine triphosphate receptors, plays a critical role in tumorigenesis. Evidence suggested that P2X4R is expressed in rat C6 glioma model, however, its role and the underlying mechanism of action are still unclear in human glioblastoma multiforme (GBM). In the current study, our aim is to examine the function and the molecular basis of P2X4R in GBM. We first observed that GBM cells, U251, T98, U87, U373, and A172 were all high expressed P2X4R, when compared with the normal human astrocytes (NHA) cells. To gain the function of P2X4R, P2X4R silence cells were constructed by transfection with P2X4R small interfering RNA (siRNA). We found that P2X4R deletion impeded T98 and U87 cell viability and proliferation, and further studies indicated that cell apoptosis and caspase‐3 activity was increased in T98 and U87 cell transfected with P2X4R siRNA. Subsequently, we confirmed that P2X4R silence suppressed brain‐derived neurotrophic factor (BDNF), Trk receptor tyrosine kinases (TrkB), and activating transcription factor 4 (ATF4) expression in T98 and U87 cells. And P2X4R siRNA–induced ATF4‐expression inhibition dependent on BDNF/TrkB signaling pathway. The impact of P2X4R silence on T98 and U87 cell growth and apoptosis was reversed by ATF4 overexpression. In summary, this study provides the first evidence that P2X4R plays important roles in GBM cell growth and apoptosis.

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“…Glioblastoma cells are known to have variable sensitivity to chemotherapeutic agents and to develop chemoresistance ( 37 – 40 ). As we used a primary GBM cell line, we first performed a dose–response study to determine IC 50 values for TMZ, carmustine, and cisplatin.…”

Section: Resultsmentioning

confidence: 99%

Downregulation of Leucine-Rich Repeat-Containing 8A Limits Proliferation and Increases Sensitivity of Glioblastoma to Temozolomide and Carmustine

et al. 2018

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BackgroundGlioblastoma (GBM) is the most common primary malignant brain tumor in adults. Ubiquitously expressed volume-regulated anion channels (VRAC) are thought to play a role in cell proliferation, migration, and apoptosis. VRAC are heteromeric channel complexes assembled from proteins belonging to the leucine-rich repeat-containing 8A (LRRC8A through E), among which LRRC8A plays an indispensable role. In the present work, we used an RNAi approach to test potential significance of VRAC and LRRC8A in GBM survival and sensitivity to chemotherapeutic agents.MethodsPrimary GBM cells were derived from a human surgical tissue sample. LRRC8A expression was determined with quantitative RT-PCR and downregulated using siRNA. The effects of LRRC8A knockdown on GBM cell viability, proliferation, and sensitivity to chemotherapeutic agents were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and Coulter counter assays. Cell cycle progression was further explored using fluorescence-activated cell sorting analysis of propidium iodide-stained cells.ResultsTemozolomide (TMZ), carmustine, and cisplatin reduced GBM cell survival with the IC50 values of ~1,250, 320, and 30 µM, respectively. Two of three tested gene-specific siRNA constructs, siLRRC8A_3 and siLRRC8A_6, downregulated LRRC8A expression by >80% and significantly reduced GBM cell numbers. The most potent siLRRC8A_3 itself reduced viable cell numbers by ≥50%, and significantly increased toxicity of the sub-IC50 concentrations of TMZ (570 µM) and carmustine (167 µM). In contrast, the effects of siLRRC8A_3 and cisplatin (32 µM) were not additive, most likely because cisplatin uptake is VRAC-dependent. The results obtained in primary GBM cells were qualitatively recapitulated in U251 human GBM cell line.ConclusionDownregulation of LRRC8A expression reduces GBM cell proliferation and increases sensitivity to the clinically used TMZ and carmustine. These findings indicate that VRAC represents a potential target for the treatment of GBM, alone or in combination with the current standard-of-care.

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The oxido-metabolic driver ATF4 enhances temozolamide chemo-resistance in human gliomas

Cited by 62 publications

References 35 publications

Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer

Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer

P2X4R silence suppresses glioma cell growth through BDNF/TrkB/ATF4 signaling pathway

Downregulation of Leucine-Rich Repeat-Containing 8A Limits Proliferation and Increases Sensitivity of Glioblastoma to Temozolomide and Carmustine

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