Lysosomal cystine governs ferroptosis sensitivity in cancer via nuclear cysteine response
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ABSTRACT:
PROVIDER: PRJNA997251 | ENA |
REPOSITORIES: ENA
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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:Excess cysteine (and cystine) is known to be toxic in organisms. Due to the absence of cysteine dioxygenase (involved in degradation of excess cysteine in humans and pathogenic fungi) in non pathogenic fungi such as S. cerevisiae, mechanism of cysteine (and cystine) tolerance is yet to be addressed.
2017-06-13 | GSE87794 | 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:Overexpression of MYC family members is linked to poor clinical outcome in many human cancers. These oncoproteins drive proliferation, alter metabolism, and mediate an antioxidant response to maintain tumor cell redox balance. However, to date, there are no effective inhibitors that specifically target MYC-amplified tumors. We demonstrate that MYCN-amplified, aggressive childhood neuroblastoma cells undergo ferroptotic cell death in vivo in the absence of intracellular cysteine, thus implicating MYCN as a predictive biomarker for ferroptosis sensitivity in neuroblastoma. Although cysteine is provided by both uptake from the microenvironment and MYCN-induced transsulfuration of methionine, glutathione levels remain low in these highly proliferative cancer cells due to concomitant cysteine utilization for protein and nucleotide synthesis. Consequently, MYCN-amplified neuroblastoma cells are highly susceptible to lipid peroxidation and ferroptosis, which must be counteracted by GPX4 activity. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. Our data show that MYCN-amplified neuroblastoma is sensitized to ferroptosis, which can be exploited therapeutically, by depleting the intracellular cysteine pool with concomitant GPX4 inactivation. These findings may help to develop novel clinical strategies to target MYCN-amplified tumors by inducing ferroptotic cell death.
2022-01-18 | GSE189174 | GEO
Project description:Differentiation is critical for epithelial cell fate decisions, but the signals involved remain unclear. The kidney proximal tubule (PT) cells reabsorb disulphide-rich proteins through endocytosis, generating cystine via lysosomal proteolysis. Here we report that defective cystine mobilization from lysosomes through cystinosin (CTNS), which is mutated in cystinosis, diverts PT cells towards growth and proliferation, disrupting their functions. Mechanistically, lysosomal cystine storage stimulates Ragulator-Rag GTPase-dependent recruitment of mechanistic target of Rapamycin complex 1 (mTORC1) and its constitutive activation. Re-introduction of CTNS restores nutrient-dependent regulation of mTORC1 in knockout cells, whereas cell-permeant analogues of L-cystine, accumulating within lysosomes, render wild-type cells resistant to nutrient withdrawal. Therapeutic mTORC1 inhibition corrects lysosome and differentiation downstream of cystine storage, and phenotypes in a zebrafish model of cystinosis. Thus, cystine serves as a lysosomal signal that tailors mTORC1 signaling and metabolism to direct epithelial cell fate decisions. These results identify mechanisms and therapeutic targets for dysregulated homeostasis in cystinosis.
2023-03-08 | GSE226396 | 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:Differentiation is critical for epithelial cell fate decisions, but the signals involved remain unclear. The kidney proximal tubule (PT) cells reabsorb disulphide-rich proteins through endocytosis, generating cystine via lysosomal proteolysis. Here we report that defective cystine mobilization from lysosomes through cystinosin (CTNS), which is mutated in cystinosis, diverts PT cells towards growth and proliferation, disrupting their functions. Mechanistically, lysosomal cystine storage stimulates Ragulator-Rag GTPase-dependent recruitment of mechanistic target of Rapamycin complex 1 (mTORC1) and its constitutive activation. Re-introduction of CTNS restores nutrient-dependent regulation of mTORC1 in knockout cells, whereas cell-permeant analogues of L-cystine, accumulating within lysosomes, render wild-type cells resistant to nutrient withdrawal. Therapeutic mTORC1 inhibition corrects lysosome and differentiation downstream of cystine storage, and phenotypes in a zebrafish model of cystinosis. Thus, cystine serves as a lysosomal signal that tailors mTORC1 signaling and metabolism to direct epithelial cell fate decisions. These results identify mechanisms and therapeutic targets for dysregulated homeostasis in cystinosis.
2023-03-08 | GSE226397 | GEO
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:MYCN mediates cysteine addiction and sensitizes to ferroptosis
| PRJNA781844 | ENA
Project description:The inherent ability of melanoma cells to alter the differentiation-associated transcriptional repertoire to evade treatment and facilitate metastatic spread is well accepted and has been termed phenotypic switching. However, how these facets of cellular behavior are controlled remains largely elusive. Here we show that cysteine availability, whether from lysosomes (CTNS-dependent) or exogenously derived (SLC7A11-dependent or as N-acetylcysteine), controls melanoma differentiation-associated pathways by acting on the melanocyte master regulator MITF. Functional data indicate that low cysteine availability reduces MITF levels and impairs lysosome functions, which affects tumor ferroptosis sensitivity but improves metastatic spread in vivo. Mechanistically, cysteine-restrictive conditions reduce acetyl-CoA levels to decrease p300-mediated H3K27 acetylation at the melanocyte-restricted MITF promoter, thus forming a cysteine feed-forward regulation that controls MITF levels and downstream lysosome functions. These findings collectively suggest that cysteine homeostasis governs melanoma differentiation by maintaining MITF levels and lysosome functions, which protect against ferroptosis and limit metastatic spread.
2024-08-16 | GSE269922 | GEO