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Cancer Biology & Medicine Jun 2023Lung oncogenesis relies on intracellular cysteine to overcome oxidative stress. Several tumor types, including non-small cell lung cancer (NSCLC), upregulate the system... (Review)
Review
Lung oncogenesis relies on intracellular cysteine to overcome oxidative stress. Several tumor types, including non-small cell lung cancer (NSCLC), upregulate the system x cystine/glutamate antiporter (xCT) through overexpression of the cystine transporter SLC7A11, thus sustaining intracellular cysteine levels to support glutathione synthesis. Nuclear factor erythroid 2-related factor 2 (NRF2) serves as a master regulator of oxidative stress resistance by regulating SLC7A11, whereas Kelch-like ECH-associated protein (KEAP1) acts as a cytoplasmic repressor of the oxidative responsive transcription factor NRF2. Mutations in KEAP1/NRF2 and p53 induce SLC7A11 activation in NSCLC. Extracellular cystine is crucial in supplying the intracellular cysteine levels necessary to combat oxidative stress. Disruptions in cystine availability lead to iron-dependent lipid peroxidation, thus resulting in a type of cell death called ferroptosis. Pharmacologic inhibitors of xCT (either SLC7A11 or GPX4) induce ferroptosis of NSCLC cells and other tumor types. When cystine uptake is impaired, the intracellular cysteine pool can be sustained by the transsulfuration pathway, which is catalyzed by cystathionine-B-synthase (CBS) and cystathionine g-lyase (CSE). The involvement of exogenous cysteine/cystine and the transsulfuration pathway in the cysteine pool and downstream metabolites results in compromised CD8 T cell function and evasion of immunotherapy, diminishing immune response and potentially reducing the effectiveness of immunotherapeutic interventions. Pyroptosis is a previously unrecognized form of regulated cell death. In NSCLCs driven by EGFR, ALK, or KRAS, selective inhibitors induce pyroptotic cell death as well as apoptosis. After targeted therapy, the mitochondrial intrinsic apoptotic pathway is activated, thus leading to the cleavage and activation of caspase-3. Consequently, gasdermin E is activated, thus leading to permeabilization of the cytoplasmic membrane and cell-lytic pyroptosis (indicated by characteristic cell membrane ballooning). Breakthroughs in KRAS G12C allele-specific inhibitors and potential mechanisms of resistance are also discussed herein.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Cystine; Cysteine; Reactive Oxygen Species; Kelch-Like ECH-Associated Protein 1; Cystathionine; NF-E2-Related Factor 2; Proto-Oncogene Proteins p21(ras); Lung Neoplasms
PubMed: 37381723
DOI: 10.20892/j.issn.2095-3941.2023.0108 -
Redox Biology Aug 2023Glioblastoma (GBM) is the most common type of adult brain tumor with extremely poor survival. Cystathionine-gamma lyase (CTH) is one of the main Hydrogen Sulfide (HS)...
PURPOSE
Glioblastoma (GBM) is the most common type of adult brain tumor with extremely poor survival. Cystathionine-gamma lyase (CTH) is one of the main Hydrogen Sulfide (HS) producing enzymes and its expression contributes to tumorigenesis and angiogenesis but its role in glioblastoma development remains poorly understood.
METHODS
and Principal Results: An established allogenic immunocompetent in vivo GBM model was used in C57BL/6J WT and CTH KO mice where the tumor volume and tumor microvessel density were blindly measured by stereological analysis. Tumor macrophage and stemness markers were measured by blinded immunohistochemistry. Mouse and human GBM cell lines were used for cell-based analyses. In human gliomas, the CTH expression was analyzed by bioinformatic analysis on different databases. In vivo, the genetic ablation of CTH in the host led to a significant reduction of the tumor volume and the protumorigenic and stemness transcription factor sex determining region Y-box 2 (SOX2). The tumor microvessel density (indicative of angiogenesis) and the expression levels of peritumoral macrophages showed no significant changes between the two genotypes. Bioinformatic analysis in human glioma tumors revealed that higher CTH expression is positively correlated to SOX2 expression and associated with worse overall survival in all grades of gliomas. Patients not responding to temozolomide have also higher CTH expression. In mouse or human GBM cells, pharmacological inhibition (PAG) or CTH knockdown (siRNA) attenuates GBM cell proliferation, migration and stem cell formation frequency.
MAJOR CONCLUSIONS
Inhibition of CTH could be a new promising target against glioblastoma formation.
Topics: Mice; Humans; Animals; Glioblastoma; Cystathionine gamma-Lyase; Mice, Inbred C57BL; Temozolomide; Cell Line; Cell Line, Tumor
PubMed: 37300955
DOI: 10.1016/j.redox.2023.102773 -
International Immunopharmacology Jul 2023The chronic articular disease osteoarthritis (OA) is characterized by osteophyte generation, subchondral bone remodeling, and cartilage deterioration. Low levels of H2S...
The chronic articular disease osteoarthritis (OA) is characterized by osteophyte generation, subchondral bone remodeling, and cartilage deterioration. Low levels of H2S catalyzed by cystathionine-γ-lyase (CSE) encoded by Cthhas neuroprotective, cardioprotective, anti-apoptotic, and anti-inflammatory effects thus, Cth is being developed as a potential therapy for the management of the pathogenesis and symptoms of osteoarthritis. Single-cell RNA sequencing (scRNA-seq) and immunohistochemistry of human cartilage revealed that the expression of CTH was decreased in OA patients. We found that Cthoverexpression decrease IL-1β-induced overactivation of the NF-κB signaling pathway. In vivo, Cthoverexpression relieved pain response and cartilage damage in the anterior cruciate ligament transection (ACLT) rat model. In vitro, CSE alleviated chondrocytes catabolism, inflammation, apoptosis, and senescence, and suppressed the NF-κB pathway. We postulate that CSE has therapeutic effects in suppressing inflammation and degeneration in OA and should be further investigated clinically.
Topics: Humans; Rats; Animals; NF-kappa B; Cystathionine; Cystathionine gamma-Lyase; Osteoarthritis; Inflammation; Pain; Chondrocytes; Cartilage, Articular; Disease Models, Animal
PubMed: 37182456
DOI: 10.1016/j.intimp.2023.110289 -
Reviews in the Neurosciences Dec 2023The transsulfuration pathway (TSP) is a metabolic pathway involving sulfur transfer from homocysteine to cysteine. Transsulfuration pathway leads to many sulfur... (Review)
Review
The transsulfuration pathway (TSP) is a metabolic pathway involving sulfur transfer from homocysteine to cysteine. Transsulfuration pathway leads to many sulfur metabolites, principally glutathione, HS, taurine, and cysteine. Key enzymes of the TSP, such as cystathionine β-synthase and cystathionine γ-lyase, are essential regulators at multiple levels in this pathway. TSP metabolites are implicated in many physiological processes in the central nervous system and other tissues. TSP is important in controlling sulfur balance and optimal cellular functions such as glutathione synthesis. Alterations in the TSP and related pathways (transmethylation and remethylation) are altered in several neurodegenerative diseases, including Parkinson's disease, suggesting their participation in the pathophysiology and progression of these diseases. In Parkinson's disease many cellular processes are comprised mainly those that regulate redox homeostasis, inflammation, reticulum endoplasmic stress, mitochondrial function, oxidative stress, and sulfur content metabolites of TSP are involved in these damage processes. Current research on the transsulfuration pathway in Parkinson's disease has primarily focused on the synthesis and function of certain metabolites, particularly glutathione. However, our understanding of the regulation of other metabolites of the transsulfuration pathway, as well as their relationships with other metabolites, and their synthesis regulation in Parkinson´s disease remain limited. Thus, this paper highlights the importance of studying the molecular dynamics in different metabolites and enzymes that affect the transsulfuration in Parkinson's disease.
Topics: Humans; Cysteine; Parkinson Disease; Sulfur; Cystathionine beta-Synthase; Glutathione
PubMed: 37409540
DOI: 10.1515/revneuro-2023-0039 -
Cell Death & Disease Sep 2023Oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) consists of latent and lytic replication phases, both of which are important for the development of KSHV-related...
Oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) consists of latent and lytic replication phases, both of which are important for the development of KSHV-related cancers. As one of the most abundant RNA modifications, N-methyladenosine (mA) and its related complexes regulate KSHV life cycle. However, the role of METTL16, a newly discovered RNA methyltransferase, in KSHV life cycle remains unknown. In this study, we have identified a suppressive role of METTL16 in KSHV lytic replication. METTL16 knockdown increased while METTL16 overexpression reduced KSHV lytic replication. METTL16 binding to and writing of mA on MAT2A transcript are essential for its splicing, maturation and expression. As a rate-limiting enzyme in the methionine-S-adenosylmethionine (SAM) cycle, MAT2A catalyzes the conversion of L-methionine to SAM required for the transmethylation of protein, DNA and RNA, transamination of polyamines, and transsulfuration of cystathionine. Consequently, knockdown or chemical inhibition of MAT2A reduced intracellular SAM level and enhanced KSHV lytic replication. In contrast, SAM treatment was sufficient to inhibit KSHV lytic replication and reverse the effect of the enhanced KSHV lytic program caused by METTL16 or MAT2A knockdown. Mechanistically, METTL16 or MAT2A knockdown increased while SAM treatment decreased the intracellular reactive oxygen species level by altering glutathione level, which is essential for efficient KSHV lytic replication. These findings demonstrate that METTL16 suppresses KSHV lytic replication by modulating the SAM cycle to maintain intracellular SAM level and redox homeostasis, thus illustrating the linkage of KSHV life cycle with specific mA modifications, and cellular metabolic and oxidative conditions.
Topics: S-Adenosylmethionine; Herpesvirus 8, Human; Methionine; Cystathionine; RNA
PubMed: 37673880
DOI: 10.1038/s41419-023-06121-3 -
The Journal of Clinical Investigation Nov 2023While the poor prognosis of glioblastoma arises from the invasion of a subset of tumor cells, little is known of the metabolic alterations within these cells that fuel...
While the poor prognosis of glioblastoma arises from the invasion of a subset of tumor cells, little is known of the metabolic alterations within these cells that fuel invasion. We integrated spatially addressable hydrogel biomaterial platforms, patient site-directed biopsies, and multiomics analyses to define metabolic drivers of invasive glioblastoma cells. Metabolomics and lipidomics revealed elevations in the redox buffers cystathionine, hexosylceramides, and glucosyl ceramides in the invasive front of both hydrogel-cultured tumors and patient site-directed biopsies, with immunofluorescence indicating elevated reactive oxygen species (ROS) markers in invasive cells. Transcriptomics confirmed upregulation of ROS-producing and response genes at the invasive front in both hydrogel models and patient tumors. Among oncologic ROS, H2O2 specifically promoted glioblastoma invasion in 3D hydrogel spheroid cultures. A CRISPR metabolic gene screen revealed cystathionine γ-lyase (CTH), which converts cystathionine to the nonessential amino acid cysteine in the transsulfuration pathway, to be essential for glioblastoma invasion. Correspondingly, supplementing CTH knockdown cells with exogenous cysteine rescued invasion. Pharmacologic CTH inhibition suppressed glioblastoma invasion, while CTH knockdown slowed glioblastoma invasion in vivo. Our studies highlight the importance of ROS metabolism in invasive glioblastoma cells and support further exploration of the transsulfuration pathway as a mechanistic and therapeutic target.
Topics: Humans; Glioblastoma; Cystathionine; Cysteine; Reactive Oxygen Species; Hydrogen Peroxide; Multiomics; Hydrogels
PubMed: 37971886
DOI: 10.1172/JCI170397 -
Free Radical Biology & Medicine Aug 2023Ischemia-reperfusion injury is a critical liver condition during hepatic transplantation, trauma, or shock. An ischemic deprivation of antioxidants and energy...
Ischemia-reperfusion injury is a critical liver condition during hepatic transplantation, trauma, or shock. An ischemic deprivation of antioxidants and energy characterizes liver injury in such cases. In the face of increased reactive oxygen production, hepatocytes are vulnerable to the reperfusion driving ROS generation and multiple cell-death mechanisms. In this study, we investigate the importance of hydrogen sulfide as part of the liver's antioxidant pool and the therapeutic potency of the hydrogen sulfide donors sodium sulfide (NaS, fast releasing) and sodium thiosulfate (STS, NaSO, slow releasing). The mitoprotection and toxicity of STS and NaS were investigated on isolated mitochondria and a liver perfusion oxidative stress model by adding text-butyl hydroperoxide and hydrogen sulfide donors. The respiratory capacity of mitochondria, hepatocellular released LDH, glutathione, and lipid-peroxide levels were quantified. In addition, wild-type and cystathionine-γ-lyase knockout mice were subjected to warm selective ischemia-reperfusion injury by clamping the main inflow for 1 h followed by reperfusion of 1 or 24 h. A subset of animals was treated with STS shortly before reperfusion. Glutathione, plasma ALT, and lipid-peroxide levels were investigated alongside mitochondrial changes in structure (electron microscopy) and function (intravital microscopy). Liver tissue necrosis quantified 24 h after reperfusion indicates the net effects of the treatment on the organ. STS refuels and protects the endogenous antioxidant pool during liver ischemia-reperfusion injury. In addition, STS-mediated ROS scavenging significantly reduced lipid peroxidation and mitochondrial damage, resulting in better molecular and histopathological preservation of the liver tissue architecture. STS prevents tissue damage in liver ischemia-reperfusion injury by increasing the liver's antioxidant pool, thereby protecting mitochondrial integrity.
Topics: Mice; Animals; Antioxidants; Hydrogen Sulfide; Reactive Oxygen Species; Chemical and Drug Induced Liver Injury, Chronic; Liver; Reperfusion Injury; Ischemia; Glutathione; Peroxides; Reperfusion; Lipids
PubMed: 37105418
DOI: 10.1016/j.freeradbiomed.2023.04.012 -
World Journal of Stem Cells Feb 2024In this editorial, we comment on the article published in the recent issue of the . They focus on stem cell preconditioning to prevent ferroptosis by modulating the...
In this editorial, we comment on the article published in the recent issue of the . They focus on stem cell preconditioning to prevent ferroptosis by modulating the cystathionine γ-lyase/hydrogen sulfide (HS) pathway as a novel approach to treat vascular disorders, particularly pulmonary hypertension. Preconditioned stem cells are gaining popularity in regenerative medicine due to their unique ability to survive by resisting the harsh, unfavorable microenvironment of the injured tissue. They also secrete various paracrine factors against apoptosis, necrosis, and ferroptosis to enhance cell survival. Ferroptosis, a regulated form of cell death characterized by iron accumulation and oxidative stress, has been implicated in various pathologies encompassing degenerative disorders to cancer. The lipid peroxidation cascade initiates and sustains ferroptosis, generating many reactive oxygen species that attack and damage multiple cellular structures. Understanding these intertwined mechanisms provides significant insights into developing therapeutic modalities for ferroptosis-related diseases. This editorial primarily discusses stem cell preconditioning in modulating ferroptosis, focusing on the cystathionase gamma/HS ferroptosis pathway. Ferroptosis presents a significant challenge in mesenchymal stem cell (MSC)-based therapies; hence, the emerging role of HS/cystathionase gamma/HS signaling in abrogating ferroptosis provides a novel option for therapeutic intervention. Further research into understanding the precise mechanisms of HS-mediated cytoprotection against ferroptosis is warranted to enhance the therapeutic potential of MSCs in clinical settings, particularly vascular disorders.
PubMed: 38455100
DOI: 10.4252/wjsc.v16.i2.64 -
Journal of Cachexia, Sarcopenia and... Dec 2023Diabetic cardiomyopathy, a distinctive complication of diabetes mellitus, has been correlated with the presence of intracellular lipid deposits. However, the intricate...
BACKGROUND
Diabetic cardiomyopathy, a distinctive complication of diabetes mellitus, has been correlated with the presence of intracellular lipid deposits. However, the intricate molecular mechanisms governing the aberrant accumulation of lipid droplets within cardiomyocytes remain to be comprehensively elucidated.
METHODS
Both obese diabetic (db/db) mice and HL-1 cells treated with 200 μmol/L palmitate and 200 μmol/L oleate were used to simulate type 2 diabetes conditions. Transmission electron microscopy is employed to assess the size and quantity of lipid droplets in the mouse hearts. Transcriptomics analysis was utilized to interrogate mRNA levels. Lipidomics and ubiquitinomics were employed to explore the lipid composition alterations and proteins participating in ubiquitin-mediated degradation in mice. Clinical data were collected from patients with diabetes-associated cardiomyopathy and healthy controls. Western blot analysis was conducted to assess the levels of proteins linked to lipid metabolism, and the biotin-switch assay was employed to quantify protein cysteine S-sulfhydration levels.
RESULTS
The administration of H S donor, NaHS, effectively restored hydrogen sulfide levels in both the cardiac tissue and plasma of db/db mice (+7%, P < 0.001; +5%, P < 0.001). Both db/db mice (+210%, P < 0.001) and diabetic patients (+83%, P = 0.22, n = 5) exhibit elevated plasma triglyceride levels. Treatment with GYY4137 effectively lowers triglyceride levels in db/db mice (-43%, P = 0.007). The expression of cystathionine gamma-lyase and HMG-CoA reductase degradation protein 1 (SYVN1) was decreased in db/db mice compared with the wild-type mice (cystathionine gamma-lyase: -31%, P = 0.0240; SYVN1: -35%, P = 0.01), and NaHS-treated mice (SYVN1: -31%, P = 0.03). Conversely, the expression of sterol regulatory element-binding protein 1 (SREBP1) was elevated (+91%, P = 0.007; +51%, P = 0.03 compared with control and NaHS-treated mice, respectively), along with diacylglycerol O-acyltransferase 1 (DGAT1) (+95%, P = 0.001; +35%, P = 0.02) and 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3) (+88%, P = 0.01; +22%, P = 0.32). Exogenous H S led to a reduction in lipid droplet formation (-48%, P < 0.001), restoration of SYVN1 expression, modification of SYVN1's S-sulfhydration status and enhancement of SREBP1 ubiquitination. Overexpression of SYVN1 mutated at Cys115 decreased SREBP1 ubiquitination and increased the number of lipid droplets.
CONCLUSIONS
Exogenous H S enhances ubiquitin-proteasome degradation of SREBP1 and reduces its nuclear translocation by modulating SYVN1's cysteine S-sulfhydration. This pathway limits lipid droplet buildup in cardiac myocytes, ameliorating diabetic cardiomyopathy.
Topics: Animals; Humans; Mice; Cystathionine gamma-Lyase; Cysteine; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Lipids; Sterol Regulatory Element Binding Protein 1; Triglycerides; Ubiquitin; Ubiquitin-Protein Ligases
PubMed: 37899701
DOI: 10.1002/jcsm.13347 -
Molecular Genetics and Metabolism... Sep 2023Cystathionine beta synthase deficiency (causing classical homocystinuria) has been associated with high-arched palates and crowded teeth, but little has been said about...
BACKGROUND
Cystathionine beta synthase deficiency (causing classical homocystinuria) has been associated with high-arched palates and crowded teeth, but little has been said about other oral health complications. Other homocystinurias (, the remethylation defects) also have had little reported in terms of oral health. Individuals with the homocystinurias have been described as having bone density issues which can correlate with oral health. Moreover, elevations in homocysteine have a theoretical impact on tooth health and the paucity of clinical reports of oral health issues in homocystinuria may be the consequence of lack of attention by the medical community.
SIGNIFICANCE
Oral health is essential to overall health. If inadequate attention is paid to the oral health complications which can be seen in homocystinurias, then appropriate referrals and attention in therapeutic guidelines will not reflect the importance of oral health.
SPECIFIC AIMS/RESEARCH QUESTION
What oral health complications are reported by individuals with homocystinurias? Do these differ according to diagnosis?
METHODS
Data were collected from patients with homocystinurias by a series of questionnaires using the RARE-X platform. All subjects were consented prior to the collection of their data. All research was performed in accordance with the Declaration of Helsinki. Demographic data were collected as the initial questionnaire and other data were collected the oral health questionnaire.
ANALYSIS
Questionnaires were opened to the community in mid-2022 and collection of data for this study ended with data submitted up to November 2022. Descriptive statistics were done. Due to the small size of the cohort, additional statistical analyses were not attempted.
RESULTS
Patients with homocystinuria, not related to cystathionine beta synthase deficiency, are reporting some tooth structure differences. The cohort taken as a whole does not have increased risk for gingivitis, but there appears to be a risk for long-term gum disease possibly due to the rate of osteoporosis/osteopenia in this population. A large number of individuals have malalignment and malocclusion of the teeth. These data highlight oral health as an important component of care in individuals with the homocystinurias as is true of the general population at large.
PubMed: 37637152
DOI: 10.1016/j.ymgmr.2023.100999