The transsulfuration pathway: a source of cysteine for glutathione in astrocytes

McBean, Gethin J.

doi:10.1007/s00726-011-0864-8

Cited by 192 publications

(143 citation statements)

References 44 publications

(55 reference statements)

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“…Cellular cysteine is primarily obtained by extracellular cysteine uptake through the glutamate/cysteine antiporter (Xc -) (6,27,28). In addition to extracellular uptake, certain mammalian cells are able to use methionine as a sulfur donor to synthesize de novo cysteine through the trans-sulfuration pathway (6,(28)(29)(30). However, mammalian cells normally depend on only one of these patterns as the major source of cysteine.…”

Section: Metabolism and Ferroptosismentioning

confidence: 99%

Metabolic networks in ferroptosis (Review)

et al. 2018

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Abstract.Ferroptosis is an iron-dependent and peroxidation-driven form of cell death associated with multiple metabolic disorders and disrupted homeostasis. A number of metabolic processes and homeostasis are affected by ferroptosis. The molecules that regulate ferroptosis are involved in metabolic pathways that regulate cysteine exploitation, glutathione state, nicotinamide adenine dinucleotide phosphate function, lipid peroxidation and iron homeostasis. The present review summarizes the metabolic networks involved in ferroptosis based on previous studies, and discusses the function of ferroptosis in pathological processes, including cancer. Finally, the clinical significance of ferroptosis is highlighted, to provide evidence for further studies.

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Section: Metabolism and Ferroptosismentioning

confidence: 99%

Metabolic networks in ferroptosis (Review)

et al. 2018

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“…In brain carcinoma cells such as glioma cells and astrocytes, most cysteine originates from the reduction process of cystine imported by xCT under normal conditions. However, when xCT is blocked or GSH is decreased, the transsulfuration pathway is activated, which insures the cysteine supply for GSH synthesis in a compensatory manner (26,27). Furthermore, CTH activity may limit cysteine synthesis via the methionine transsulfuration pathway (28,29).…”

Section: Erastin Sensitizes Glioblastoma Cells To Temozolomide By Resmentioning

confidence: 99%

Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function

et al. 2015

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Abstract. Glioblastoma multiforme (GBM) is one of the most common encephalic malignant tumors. Due to a high recurrence rate and a lack of effective treatments, the average survival rate remains low. Temozolomide (TMZ), a class of alkylating agent, is widely used as a first-line therapeutic drug during the adjuvant treatment for GBM patients. However, most patients exhibit a palpable resistance to TMZ treatment. Additionally, the underlying mechanism remains to be clarified. In this study, glutathione (GSH) and reactive oxygen species (ROS) levels were found to be closely associated with the sensitivity of GBM cells to TMZ. We also found that TMZ markedly induced xCT, the subunit of glutamate/cystine transporter system x c -expression, which together with the GSH synthesis was increased while the TMZ-inducible ROS level was decreased in GBM cells. In addition, the cystathionine γ-lyase (CTH) acivity, a key enzyme in the transsulfuration pathway was enhanced by TMZ, which insured a cysteine supply and GSH synthesis in a compensatory manner when xCT was blocked. Thus, the individual inhibition of xCT by siRNA and a pharmacological inhibitor (sulfasalazine) only partially inhibited GSH synthesis and moderately enhanced the GBM cell sensitivity to TMZ. However, the TMZ-induced cytotoxicity was markedly increased along with a marked decrease in GSH levels as result of co-treatment with erastin, which inhibited cysteine uptake from xCT transporter and suppressed CTH activity, leading to impaired transformation from methionine to cysteine. In conclusion, to GBM therapy with a drug combination of TMZ and erastin may be beneficial.

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“…1). In fact, not only CARS knockdown, but also CONTACT Brent R. Stockwell bstockwell@columbia.edu; Kenichi Shimada ks2474@columbia.edu inhibition of some other tRNA synthetases (ARS), including histidyl-tRNA synthetases (HARS) or glutamyl prolyl-tRNA synthetases (EPRS), were also shown to activate the transsulfuration pathway and rescue cells from erastin-induced ferroptosis; transcriptional expression of cystathionine-b-synthase (CBS), a rate-limiting enzyme of the pathway, 8 was significantly upregulated in response to knockdown of these genes. The suppressive effect of their knockdown on ferroptosis disappeared when the transsulfuration pathway was pharmacologically or genetically inhibited, confirming that ARS knockdown activates the transsulfuration pathway as a mechanism for preventing ferroptosis.…”

mentioning

confidence: 99%

tRNA synthase suppression activatesde novocysteine synthesis to compensate for cystine and glutathione deprivation during ferroptosis

Shimada

Stockwell

2015

Molecular & Cellular Oncology

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The transsulfuration pathway: a source of cysteine for glutathione in astrocytes

Abstract: Publication informationAmino Acids, 42 (1): 199-205Publisher Springer Item record/more information

Cited by 192 publications

References 44 publications

Metabolic networks in ferroptosis (Review)

Metabolic networks in ferroptosis (Review)

Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function

tRNA synthase suppression activatesde novocysteine synthesis to compensate for cystine and glutathione deprivation during ferroptosis

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