Physiological response of S. cerevisiae excess cysteine or cystine
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ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE87794 | GEO | 2017/06/13
SECONDARY ACCESSION(S): PRJNA347626
REPOSITORIES: GEO
Similar Datasets
Project description:The amino acid cysteine and its oxidized dimeric form cystine are commonly believed to be synonymous in metabolic functions. Cyst(e)ine depletion not only induces amino acid response, but also triggers ferroptosis, a non-apoptotic cell death. Here we report that, unlike general amino acid starvation, cyst(e)ine deprivation triggers ATF4 induction at the transcriptional level. Unexpectedly, it is the shortage of lysosomal cystine, but not the cytosolic cysteine, that elicits the adaptative ATF4 response. The lysosome-nucleus signaling pathway involves the aryl hydrocarbon receptor (AhR) that senses lysosomal cystine via the kynurenine pathway. A blockade of lysosomal cystine efflux attenuates ATF4 induction and sensitizes ferroptosis. To potentiate ferroptosis in cancer, we develop a synthetic mRNA reagent CysRx that converts cytosolic cysteine to lysosomal cystine. CysRx maximizes cancer cell ferroptosis and effectively suppresses tumor growth in vivo. Thus, intracellular nutrient reprogramming has the potential to induce selective ferroptosis in cancer without systematic perturbation.
2023-08-30 | GSE237928 | GEO
Project description:Metabolic reprogramming is a hallmark of human cancer and cancer-specific metabolism provide opportunities for cancer diagnosis, prognosis, and treatment. However, how metabolic pathways affect the initiation and progression of colorectal cancer remain largely unknown. Here, we showed cysteine is highly enriched in colorectal tumors compared with adjacent non-tumor tissues to promote tumorigenesis of CRC. Both cystine and cysteine imports are essential to maintain intracellular cysteine level and promote tumor growth and survival. Transporter genes of cystine and cysteine are all upregulated in colorectal cancer by tumor microenvironment induced ROS through transcription factor ATF4. Glutathione synthetase GSS is upregulated and increases cysteine to reduced glutathione flux to support tumor growth and survival in colorectal cancer. Depletion of cystine and cysteine by a recombinant cyst(e)inase effectively reduced the growth of colorectal tumors. Moreover, scavenging cystine and cysteine induces autophagy of colorectal cancer cells through mTOR-ULK signaling axis. With this study, we demonstrate that cysteine metabolism is a key signature of CRC metabolic reprogramming and targeting cysteine metabolism might be an effective approach to treat colon cancer.
2023-01-21 | GSE223118 | GEO
Project description:Metabolic reprogramming is a hallmark of human cancer and cancer-specific metabolism provide opportunities for cancer diagnosis, prognosis, and treatment. However, how metabolic pathways affect the initiation and progression of colorectal cancer remain largely unknown. Here, we showed cysteine is highly enriched in colorectal tumors compared with adjacent non-tumor tissues to promote tumorigenesis of CRC. Both cystine and cysteine imports are essential to maintain intracellular cysteine level and promote tumor growth and survival. Transporter genes of cystine and cysteine are all upregulated in colorectal cancer by tumor microenvironment induced ROS through transcription factor ATF4. Glutathione synthetase GSS is upregulated and increases cysteine to reduced glutathione flux to support tumor growth and survival in colorectal cancer. Depletion of cystine and cysteine by a recombinant cyst(e)inase effectively reduced the growth of colorectal tumors. Moreover, scavenging cystine and cysteine induces autophagy of colorectal cancer cells through mTOR-ULK signaling axis. With this study, we demonstrate that cysteine metabolism is a key signature of CRC metabolic reprogramming and targeting cysteine metabolism might be an effective approach to treat colon cancer.
2023-01-21 | GSE223119 | GEO
Project description:Triple-negative breast cancer (TNBC) has a highly aggressive nature and distinct molecular characteristics from other subtypes of breast cancer and lacks effective targeted therapy. The molecular and genetic basis of cysteine/cystine dependency in TNBC is complex. We found that cysteine addiction associates with the expression of a set of Claudin genes in TNBC. The Claudin-high TNBCs are independent on cystine, while the Claudin-low TNBCs undergo rapid ferroptosis upon cystine deprivation or inhibition of cystine transport by erastin. To overcome the resistance of Claudin-high TNBC and luminal breast cancer to the potential targeted cystine-addiction therapy, we explored the synthetic lethality of cysteine by an epigenetic compound library screen. Several potent HDAC6 inhibitors were identified and rendered the Claudin-high TNBCs and luminal cancer cells dependent on extracellular cystine and undergoing ferroptosis upon cystine deprivation. The transcriptomic profiling showed that the HDAC6 inhibitor tubacin in combination with erastin activates a synthetic-lethal transcriptional program. Together, we have identified the HDAC6 inhibitors as potent therapy-sensitizers to revive the targeted cysteine-addiction therapy for various subtypes of breast cancer, not limit in the Claudin-low TNBC.
2021-06-02 | GSE154425 | GEO
Project description:Cysteine is a semi-essential amino acid provided by dietary intake of mainly meat, eggs and whole grains or via the amino acid methionine. The majority of dietary cystine is absorbed in the small intestine and can be used for protein synthesis or converted to taurine and glutathione. Since there is a trend towards adopting a vegetarian/vegan diet, which is low in cysteine, in this study, we investigate the effect of dietary cystine restriction on intestinal epithelial layer function. Mice (8/group) received a normal diet or a diet low in cystine for 2 weeks. We observed no changes in plasma methionine, cysteine, taurine or glutathione levels after 2 weeks. Stem cell markers as well as the proliferation marker Ki67 were or tended to be increased upon cystine restriction. Gene set enrichment analysis reveals enrichment of Wnt signaling in the small intestine of mice on the low cystine diet. These proliferative effects were not observed in the colon, and are thus specific for the small intestine. In the colon, we observed that dietary cystine restriction results in an increase in the number of goblet cells but no significant changes in the thickness of the mucus barrier or in its protective capacity. There was no difference in the microbiome between the normal and low cystine diet. Overall, we cannot conclude if dietary cystine restriction is beneficial, since increased proliferation and goblet cells can indicate a potential for damage repair, nevertheless hyperproliferation has the potential to induce cancer as well.
2023-09-01 | GSE234566 | GEO
Project description:Physiological response of S. cerevisiae excess cysteine or cystine
| PRJNA347626 | ENA
Project description:Here, gene profiles in rat spermatogonial stem cell lines are compared to publicly available mouse, monkey and human spermatogonial gene profiles. Interestingly, rat spermatogonia expressed metabolic control factors Foxa1, Foxa2 and Foxa3. Germline Foxa2 was enriched in Gfra1Hi and Gfra1Low undifferentiated A-single spermatogonia. Foxa2-bound loci in spermatogonial chromatin were over-represented by conserved stemness genes (Dusp6, Gfra1, Etv5, Rest, Nanos2, Foxp1) that intersect bioinformatically with conserved glutathione/pentose phosphate metabolism genes (Tkt, Gss, Gclc, Gclm, Gpx1, Gpx4, Fth), marking elevated spermatogonial GSH:GSSG. Cystine-uptake and intracellular conversion to cysteine typically couple glutathione biosynthesis to pentose phosphate metabolism. Rat spermatogonia, curiously, displayed poor germline stem cell viability in cystine-containing media, and, like primate spermatogonia, exhibited reduced transsulfuration pathway markers. Exogenous cysteine, cysteine-like mercaptans, somatic testis cells and ferroptosis inhibitors counteracted the cysteine starvation-induced spermatogonial death and stimulated spermatogonial growth factor activity in vitro.
2020-12-17 | GSE163302 | GEO
Project description:Analysis of ferroptosis markers from cells isolated from neuroblastoma orthotopic xenograft mouse model. We combine simultaneous inhibition of cysteine uptake and transsulfuration in xenograft model using SK-N-DZ cell line. We treated the mice with IKE and PPG together with genetic targeting of GPX4 activity. At the end of the treatment, transcriptional profiling of residual small tumors revealed induction of ferroptosis markers after combined inhibition of cystine uptake/cysteine synthesis and GPX4 as compared to tumors treated with vehicle control.
2022-01-05 | GSE192976 | GEO
Project description:It has remained unknown how cells reduce cystine taken up from the extracellular space, which is a required step for further utilization of cysteine in key processes such as protein or glutathione synthesis. Here we show that the thioredoxin-related protein of 14 kDa (TRP14, encoded by TXNDC17) is the rate limiting enzyme for intracellular cystine reduction. When TRP14 is genetically knocked out, cysteine synthesis through the transsulfuration pathway becomes the major source of cysteine in human cells, and knockout of both pathways becomes lethal in C. elegans subjected to proteostatic stress. TRP14 can also reduce cysteinyl moieties on proteins, rescuing their activities as here shown with cysteinylated peroxiredoxin 2. Txndc17 knock-out mice were, surprisingly, protected in an acute pancreatitis model, concomitant with activation of Nrf2-driven antioxidant pathways and upregulation of transsulfuration. We conclude that TRP14 is the evolutionary conserved enzyme principally responsible for intracellular cystine reduction in C. elegans, mice and humans.
2024-05-10 | PXD050368 | Pride
Project description:Purpose: To identify differentially expressed genes regulated by cystine. Methods: HCT116 or RKO cells were cultured for 48 hours in cystine-free or 25μM cystine-containing conditional media, and three independent samples were collected by Trizol reagent and subjected to mRNA-sequencing by the LC Bio (Zhejiang, China) and data analysis Results: we identified cystine upregulated 145 genes and downregulated 169 genes in both HCT116 and RKO cells. GO enrichment analysis revealed that cystine regulated biological functions of G1/S transition of mitotic cell cycle and regulation of DNA replication biosynthetic process.In addition, KEGG enrichment analysis showed that mammalian target of rapamycin (mTOR) signaling pathway, a well-known nutrient sensor, was regulated by cystine. Furthermore,we noticed that SESN2 was one of the most significantly downregulated genes by cystine in both cell lines, and confirmed that cystine activates mTORC1 via the GCN2-ATF4-SESN2 axis in colon cancer cells. Conclusions: Our study established that cystine activates mTORC1 through GCN2-ATF4-SESN2 axis.
2021-04-16 | GSE157894 | GEO