Hypoxia-induced cysteine metabolism reprogramming are crucial for the tumorigenesis of colorectal cancer [HCT116]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE223118 | GEO | 2023/01/21
REPOSITORIES: GEO
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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: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:In this study, we combined metabolic reconstruction, growth assays, metabolome and transcriptome analyses to obtain a global view of the sulfur metabolic network and of the response to sulfur availability in Brevibacterium aurantiacum. In agreement with the growth of B. aurantiacum in the presence of sulfate and cystine, the metabolic reconstruction showed the presence of a sulfate assimilation pathway and of thiolation pathways that produce cysteine (cysE and cysK) or homocysteine (metX and metY) from sulfide, of at least one gene of the transsulfuration pathway (aecD) and of genes encoding three MetE-type methionine synthases. We also compared the expression profiles of B. aurantiacum ATCC9175 during sulfur starvation and in the presence of sulfate, cystine or methionine plus cystine. In sulfur starvation, 690 genes including 21 genes involved in sulfur metabolism and 29 genes encoding amino acids and peptide transporters were differentially expressed. We also investigated changes in pools of sulfur-containing metabolites and in expression profiles after growth in the presence of sulfate, cystine or methionine plus cystine. The expression of genes involved in sulfate assimilation and cysteine synthesis was repressed in presence of cysteine, while the expression of metX, metY, metE1, metE2 and BL613 encoding a probable cystathionine-γ-synthase decreased in the presence of methionine. We identified three ABC transporters: two stronger transcribed during cysteine limitation and one during methionine depletion. Finally, the expression of genes encoding a methionine γ-lyase, BL929, and a methionine transporter (metPS) was induced in the presence of methionine, in conjunction with a significant increase of volatile sulfur compounds production. Refer to individual Series. This SuperSeries is composed of the following subset Series: GSE25418: BA-Methionine plus Cystine vs Cystine GSE25419: BA-Sulfate vs Cystine GSE25420: BA-Methionine plus Cystine vs Sulfate GSE25421: BA-Sulfate vs Sulfate starvation
2010-11-25 | E-GEOD-25422 | biostudies-arrayexpress
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:Mutations in cancer reprogram amino acid metabolism to drive tumor growth, but the molecular mechanisms are not well understood. Using an unbiased proteomic screen, we identified mTORC2 as a critical regulator of amino acid metabolism in cancer via phosphorylation of the cystine-glutamate antiporter xCT. mTORC2 phosphorylates serine 26 at the cytosolic N-terminus of xCT, inhibiting its activity. Genetic inhibition of mTORC2, or pharmacologic mTOR kinase inhibition, promotes glutamate secretion, cystine uptake and incorporation into glutathione linking growth factor receptor signaling with amino acid uptake and utilization. These results identify an unanticipated mechanism of amino acid metabolic reprogramming in cancer, enabling tumor cells to adapt to changing environmental conditions.
2017-06-28 | PXD006461 | Pride
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:Altered metabolism is an important part of malignant transformation of tumor cells. Oncogenic transformation may reprogram tumor metabolism and render tumor cells addicted to extracellular nutrients. Such nutrient addictions associated with oncogenic mutations may offer therapeutic opportunities; however, it remains difficult to predict these nutrient addictions. Here, we performed a nutrigenetic screen to determine the phenotypes of isogenic pairs of clear-cell renal cancer cells (ccRCC) with or without VHL upon the deprivation of individual amino acids. We identified that cystine deprivation triggered rapid programmed necrosis in VHL-deficient RCC, but not in their VHL-restored counterparts. Similar cystine addiction was also observed in VHL-deficient primary RCC tumors cells. Blockage of cystine uptake significantly delayed xenograft growth of ccRCC. Importantly, cystine deprivation triggered similar metabolic changes regardless of VHL status. Therefore, metabolic differences due to cystine deprivation are not different enough to readily explain the distinct fate of life vs. death in VHL-deficient and restored cell.. Instead, we found that increased levels of TNFα associated with VHL loss in the VHL-deficient RCC force them to rely on intact RIPK1 to inhibit apoptosis. However, this pre-existing elevated TNFα in the VHL-deficient ccRCC renders these cells susceptible to the necrosis signaling triggered by cystine deprivation. In addition, we identified that cystine-deprived necrosis in VHL-deficient RCC depends on reciprocal amplification of the Src-p38-Noxa signaling and TNFα-RIP1/3-MLKL necrosis pathways that culminate in MLKL oligomerization and programmed necrosis. Together, our data reveal that the contextual cystine-addictions in VHL-deficient ccRCC is dependent on activating pre-existing oncogenic pathways to trigger programmed necrosis. RNA was extracted by RNAeasy kits (Qiagen) from the RCC4 Vec and VHL-reconstituted cells which were exposed to the control full DMEM or cystine deprived DMEM media for 6 hours (three replicates in each condition).
2016-07-01 | E-GEOD-60422 | biostudies-arrayexpress
Project description:Emerging evidence indicates that metabolic enzymes perform moonlighting functions during tumor progression, including the modulation of chemoresistance. However, the underlying mechanisms of these functions remain elusive. In this study, utilizing a genome-scale metabolic CRISPR-Cas9 knockout library screen, we observed that loss of Glutamate-cysteine ligase modifier subunit (GCLM), a rate-limiting enzyme in glutathione biosynthesis, noticeably heightens the sensitivity of colorectal cancer (CRC) cells to platinum-based chemotherapy. Mechanistically, we unveil a noncanonical mechanism through which nuclear GCLM competitively interacts with NF-kappa-B-repressing factor (NKRF), a known inhibitor of NF-κB signaling, to promote NF-κB activity and subsequently facilitate chemoresistance. In response to platinum drug treatment, P38 phosphorylates GCLM at T17, resulting in its recognition by importin a5 and subsequent nuclear translocation. Furthermore, elevated expression of nuclear GCLM is evident in CRC tissues and correlates with poor prognosis and heightened P38 activity. Overall, our findings shed light on the essential nonmetabolic role and posttranslational regulatory mechanism of GCLM in enhancing NF-κB activity and subsequent chemoresistance.
2024-01-28 | GSE254136 | 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:Claret2009 - Predicting phase III overall survival in colorectal cancer
This model is described in the article:
Model-based prediction of
phase III overall survival in colorectal cancer on the basis of
phase II tumor dynamics.
Claret L, Girard P, Hoff PM, Van
Cutsem E, Zuideveld KP, Jorga K, Fagerberg J, Bruno R.
J. Clin. Oncol. 2009 Sep; 27(25):
4103-4108
Abstract:
PURPOSE: We developed a drug-disease simulation model to
predict antitumor response and overall survival in phase III
studies from longitudinal tumor size data in phase II trials.
METHODS: We developed a longitudinal exposure-response
tumor-growth inhibition (TGI) model of drug effect (and
resistance) using phase II data of capecitabine (n = 34) and
historical phase III data of fluorouracil (FU; n = 252) in
colorectal cancer (CRC); and we developed a parametric survival
model that related change in tumor size and patient
characteristics to survival time using historical phase III
data (n = 245). The models were validated in simulation of
antitumor response and survival in an independent phase III
study (n = 1,000 replicates) of capecitabine versus FU in CRC.
RESULTS: The TGI model provided a good fit of longitudinal
tumor size data. A lognormal distribution best described the
survival time, and baseline tumor size and change in tumor size
from baseline at week 7 were predictors (P < .00001).
Predicted change of tumor size and survival time distributions
in the phase III study for both capecitabine and FU were
consistent with observed values, for example, 431 days (90%
prediction interval, 362 to 514 days) versus 401 days observed
for survival in the capecitabine arm. A modest survival
improvement of 39 days (90% prediction interval, -21 to 110
days) versus 35 days observed was predicted for capecitabine.
CONCLUSION: The modeling framework successfully predicted
survival in a phase III trial on the basis of capecitabine
phase II data in CRC. It is a useful tool to support
end-of-phase II decisions and design of phase III studies.
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2017-08-31 | MODEL1708310001 | BioModels