GADD45A: With or without you.
Medicinal research reviews
The growth arrest and DNA damage inducible (GADD)45 family includes three small and ubiquitously distributed proteins (GADD45A, GADD45B, and GADD45G) that regulate numerous cellular processes associated with stress signaling and injury response. Here, we provide a comprehensive review of the current literature investigating GADD45A, the first discovered member of the family. We first depict how its levels are regulated by a myriad of genotoxic and non-genotoxic stressors, and through the combined action of intricate transcriptional, posttranscriptional, and even, posttranslational mechanisms. GADD45A is a recognized tumor suppressor and, for this reason, we next summarize its role in cancer, as well as the different mechanisms by which it regulates cell cycle, DNA repair, and apoptosis. Beyond these most well-known actions, GADD45A may also influence catabolic and anabolic pathways in the liver, adipose tissue and skeletal muscle, among others. Not surprisingly, GADD45A may trigger AMP-activated protein kinase activity, a master regulator of metabolism, and is known to act as a transcriptional coregulator of numerous nuclear receptors. GADD45A has also been reported to display a cytoprotective role by regulating inflammation, fibrosis and oxidative stress in several organs and tissues, and is regarded an important contributor for the development of heart failure. Overall data point to that GADD45A may play an important role in metabolic, neurodegenerative and cardiovascular diseases, and also autoimmune-related disorders. Thus, the potential mechanisms by which dysregulation of GADD45A activity may contribute to the progression of these diseases are also reviewed below.
10.1002/med.22015
Disulfidptosis: A Novel Prognostic Criterion and Potential Treatment Strategy for Diffuse Large B-Cell Lymphoma (DLBCL).
International journal of molecular sciences
Diffuse Large B-cell Lymphoma (DLBCL), with its intrinsic genetic and epigenetic heterogeneity, exhibits significantly variable clinical outcomes among patients treated with the current standard regimen. Disulfidptosis, a novel form of regulatory cell death triggered by disulfide stress, is characterized by the collapse of cytoskeleton proteins and F-actin due to intracellular accumulation of disulfides. We investigated the expression variations of disulfidptosis-related genes (DRGs) in DLBCL using two publicly available gene expression datasets. The initial analysis of DRGs in DLBCL (GSE12453) revealed differences in gene expression patterns between various normal B cells and DLBCL. Subsequent analysis (GSE31312) identified DRGs strongly associated with prognostic outcomes, revealing eight characteristic DRGs (, , , , , , , ). Based on these DRGs, DLBCL patients were stratified into three groups, indicating that (1) DRGs can predict prognosis, and (2) DRGs can help identify novel therapeutic candidates. This study underscores the significant role of DRGs in various biological processes within DLBCL. Assessing the risk scores of individual DRGs allows for more precise stratification of prognosis and treatment strategies for DLBCL patients, thereby enhancing the effectiveness of clinical practice.
10.3390/ijms25137156
: a pan-cancer biomarker and disulfidptosis regulator.
Translational cancer research
Background:Elevated expression of SLC7A11, in conjunction with glucose deprivation, has revealed disulfidptosis as an emerging cell death modality. However, the prevalence of disulfidptosis across tumor cell lines, irrespective of SLC7A11 levels, remains uncertain. Additionally, deletion of the ribophorin I () gene imparts resistance to disulfidptosis, yet the precise mechanism linking to disulfidptosis remains elusive. The aim of this study is to determine the mechanism of -induced disulfidptosis and to determine the possibility of RPN1 as a pan-cancer marker. Methods:We hypothesized the widespread occurrence of disulfidptosis in various tumor cells, and proposed that -mediated disulfidptosis may be executed through cell skeleton breakdown. Experimental validation was conducted via flow cytometry, immunofluorescence, and western blot techniques. Furthermore, given 's status as an emerging cell death marker, we utilized bioinformatics to analyze its expression in tumor tissues, clinical relevance, mechanisms within the tumor microenvironment, and potential for immunotherapy. Results:Conducting experiments on breast cancer (MDA-MB-231) and lung cancer (A549) cell lines under glucose-starved conditions, we found that primarily induces cell skeleton breakdown to facilitate disulfidptosis. demonstrated robust messenger RNA (mRNA) expression across 16 solid tumors, validated by data from 12 tumor types in the Gene Expression Omnibus (GEO). Across 12 cancer types, exhibited significant diagnostic potential, particularly excelling in accuracy for glioblastoma (GBM). Elevated expression in tumor tissues was found to correlate with improved overall survival (OS) in certain cancers [diffuse large B-cell lymphoma (DLBC) and thymoma (THYM)] but poorer prognosis in others [adrenocortical carcinoma (ACC), kidney chromophobe (KICH), brain lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), and pancreatic adenocarcinoma (PAAD)]. is enriched in immune-related pathways and correlates with immune scores in tumor tissues. In urothelial carcinoma (UCC), demonstrates potential in predicting the efficacy of anti-programmed cell death ligand 1 (PD-L1) immune therapy. Conclusions:This study underscores 's role in facilitating disulfidptosis, its broad relevance as a pan-cancer biomarker, and its association with the efficacy of anti-PD-L1 immune therapy.
10.21037/tcr-24-581
Expression and prognosis analyses of the fibronectin type-III domain-containing (FNDC) protein family in human cancers: A Review.
Medicine
Despite advancements in early detection and treatment, cancer continues to pose a threat to human health and is the leading cause of death worldwide. According to recent research, the fibronectin type-III domain-containing (FNDC) protein family has been implicated in several different human disorders. However, little is known regarding their expression and prognostic significance in most human malignancies. We carried out a thorough cancer vs. normal expression study using the Oncomine and Tumor Immune Estimation Resource (TIMER) databases, as well as a prognostic evaluation using the Kaplan-Meier (KM) plotter and PrognoScan databases. Oncomine revealed that the mRNA expression levels of FNDC1, FNDC3A, and FNDC3B were higher in most malignancies than in normal tissues, but the mRNA expression levels of FNDC4, FNDC5, FNDC7, and FNDC8 were downregulated in most cancers when compared with normal tissues. In survival analyses based on KM Plotter and PrognoScan, all members of the FNDC family displayed significant correlations with survival outcomes in breast, gastric, and ovarian cancers. Furthermore, the whole FNDC family, except for FNDC7 and FNDC8, was found to have substantial predictive effects in lung adenocarcinoma, but not in squamous cell lung cancer. In addition, potential connections between several FNDC family members and survival results in liver and colorectal malignancies were discovered in this study. One or more members of the FNDC family demonstrated statistically significant differences in expression between cancer and normal tissues, suggesting that they could be used as prognostic biomarkers for specific cancers.
10.1097/MD.0000000000031854
GADD45 in Stress Signaling, Cell Cycle Control, and Apoptosis.
Advances in experimental medicine and biology
GADD45 is a gene family consisting of GADD45A, GADD45B, and GADD45G that is often induced by DNA damage and other stress signals associated with growth arrest and apoptosis. Many of these roles are carried out via signaling mediated by p38 mitogen-activated protein kinases (MAPKs). The GADD45 proteins can contribute to p38 activation either by activation of upstream kinase(s) or by direct interaction, as well as suppression of p38 activity in certain cases. In vivo, there are important tissue and cell type specific differences in the roles for GADD45 in MAPK signaling. In addition to being p53-regulated, GADD45A has also been found to contribute to p53 activation via p38. Like other stress and signaling proteins, GADD45 proteins show complex regulation and numerous effectors. More recently, aberrant GADD45 expression has been found in several human cancers, but the mechanisms behind these findings largely remain to be understood.
10.1007/978-3-030-94804-7_1
Identification of diagnostic gene signatures and molecular mechanisms for non-alcoholic fatty liver disease and Alzheimer's disease through machine learning algorithms.
Clinica chimica acta; international journal of clinical chemistry
BACKGROUND:Non-alcoholic fatty liver disease (NAFLD) and Alzheimer's disease (AD) pose significant global health challenges. Recent studies have suggested a link between these diseases; however, the underlying mechanisms remain unclear. This study aimed to decode the shared molecular landscapes of NAFLD and AD using bioinformatic approaches. METHODS:We analyzed three datasets for NAFLD and AD from the Gene Expression Omnibus (GEO). This study involved identifying differentially expressed genes (DEGs), using weighted gene co-expression network analysis (WGCNA), and using machine learning for biomarker discovery. The diagnostic biomarkers were validated using expression analysis, receiver operating characteristic (ROC) curves, and nomogram models. Furthermore, Gene Set Enrichment Analysis (GSEA) and CIBERSORT were used to investigate molecular pathways and immune cell distributions related to GADD45G and NUPR1. RESULTS:This study identified 14 genes that are common to NAFLD and AD. Machine learning identified six biomarkers for NAFLD, four for AD, and two crucial shared biomarkers: GADD45G and NUPR1. Validation confirmed their expression patterns and robust predictive abilities. GSEA revealed the intricate roles of these biomarkers in disease-associated pathways. Immune cell profiling highlighted the importance of macrophages under these conditions. CONCLUSION:This study highlights GADD45G and NUPR1 as key biomarkers for NAFLD and AD, and provides novel insights into their molecular connections. These findings revealed potential therapeutic targets, particularly in macrophage-mediated pathways, thus enriching our understanding of these complex diseases.
10.1016/j.cca.2024.117892
Gadd45 stress sensors in malignancy and leukemia.
Critical reviews in oncogenesis
Gadd45 proteins, including Gadd45a, Gadd45b, and Gadd45g, have been implicated in stress signaling in response to physiological and environmental stress, including oncogenic stress, which can result in cell cycle arrest, DNA repair, cell survival, senescence, and apoptosis. The function of Gadd45 as a stress sensor is mediated via a complex interplay of physical interactions with other cellular proteins implicated in cell cycle regulation and the response of cells to stress, notably PCNA, p21, cdc2/cyclinB1, and the p38 and JNK stress response kinases. Altered expression of Gadd45 has been observed in multiple types of solid tumors as well as in hematopoietic malignancies. Using genetically engineered mouse models and bone-marrow transplantation, evidence has been obtained indicating that Gadd45 proteins can function to either promote or suppress tumor development and leukemia; this is dependent on the molecular nature of the activated oncogene and the cell type, via engagement of different signaling pathways.
10.1615/critrevoncog.v16.i1-2.120
The stress-responsive gene GADD45G is a functional tumor suppressor, with its response to environmental stresses frequently disrupted epigenetically in multiple tumors.
Ying Jianming,Srivastava Gopesh,Hsieh Wen-Son,Gao Zifen,Murray Paul,Liao Shuen-Kuei,Ambinder Richard,Tao Qian
Clinical cancer research : an official journal of the American Association for Cancer Research
The CpG island of GADD45G was identified as a target sequence during the identification of hypermethylated genes using methylation-sensitive representational difference analysis combined with 5-aza-2'-deoxycytidine demethylation. Located at the commonly deleted region 9q22, GADD45G is a member of the DNA damage-inducible gene family. In response to stress shock, GADD45G inhibits cell growth and induces apoptosis. Same as other GADD45 members, GADD45G is ubiquitously expressed in all normal adult and fetal tissues. However, its transcriptional silencing or down-regulation and promoter hypermethylation were frequently detected in tumor cell lines, including 11 of 13 (85%) non-Hodgkin's lymphoma, 3 of 6 (50%) Hodgkin's lymphoma, 8 of 11 (73%) nasopharyngeal carcinoma, 2 of 4 (50%) cervical carcinoma, 5 of 17 (29%) esophageal carcinoma, and 2 of 5 (40%) lung carcinoma and other cell lines but not in any immortalized normal epithelial cell line, normal tissue, or peripheral blood mononuclear cells. The silencing of GADD45G could be reversed by 5-aza-2'-deoxycytidine or genetic double knockout of DNMT1 and DNMT3B, indicating a direct epigenetic mechanism. Aberrant methylation was further frequently detected in primary lymphomas although less frequently in primary carcinomas. Only one single sequence change in the coding region was detected in 1 of 25 cell lines examined, indicating that genetic inactivation of GADD45G is very rare. GADD45G could be induced by heat shock or UV irradiation in unmethylated cell lines; however, this stress response was abolished when its promoter becomes hypermethylated. Ectopic expression of GADD45G strongly suppressed tumor cell growth and colony formation in silenced cell lines. These results show that GADD45G can act as a functional new-age tumor suppressor but being frequently inactivated epigenetically in multiple tumors.
10.1158/1078-0432.CCR-05-0267
Cytokine-regulated GADD45G induces differentiation and lineage selection in hematopoietic stem cells.
Stem cell reports
The balance of self-renewal and differentiation in long-term repopulating hematopoietic stem cells (LT-HSC) must be strictly controlled to maintain blood homeostasis and to prevent leukemogenesis. Hematopoietic cytokines can induce differentiation in LT-HSCs; however, the molecular mechanism orchestrating this delicate balance requires further elucidation. We identified the tumor suppressor GADD45G as an instructor of LT-HSC differentiation under the control of differentiation-promoting cytokine receptor signaling. GADD45G immediately induces and accelerates differentiation in LT-HSCs and overrides the self-renewal program by specifically activating MAP3K4-mediated MAPK p38. Conversely, the absence of GADD45G enhances the self-renewal potential of LT-HSCs. Videomicroscopy-based tracking of single LT-HSCs revealed that, once GADD45G is expressed, the development of LT-HSCs into lineage-committed progeny occurred within 36 hr and uncovered a selective lineage choice with a severe reduction in megakaryocytic-erythroid cells. Here, we report an unrecognized role of GADD45G as a central molecular linker of extrinsic cytokine differentiation and lineage choice control in hematopoiesis.
10.1016/j.stemcr.2014.05.010
Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms.
Nature communications
Despite the identification of driver mutations leading to the initiation of myeloproliferative neoplasms (MPNs), the molecular pathogenesis of MPNs remains incompletely understood. Here, we demonstrate that growth arrest and DNA damage inducible gamma (GADD45g) is expressed at significantly lower levels in patients with MPNs, and JAK2V617F mutation and histone deacetylation contribute to its reduced expression. Downregulation of GADD45g plays a tumor-promoting role in human MPN cells. Gadd45g insufficiency in the murine hematopoietic system alone leads to significantly enhanced growth and self-renewal capacity of myeloid-biased hematopoietic stem cells, and the development of phenotypes resembling MPNs. Mechanistically, the pathogenic role of GADD45g insufficiency is mediated through a cascade of activations of RAC2, PAK1 and PI3K-AKT signaling pathways. These data characterize GADD45g deficiency as a novel pathogenic factor in MPNs.
10.1038/s41467-024-47297-2
GADD45g acts as a novel tumor suppressor, and its activation suggests new combination regimens for the treatment of AML.
Guo Dan,Zhao Yangyang,Wang Nan,You Na,Zhu Wenqi,Zhang Peiwen,Ren Qian,Yin Jing,Cheng Tao,Ma Xiaotong
Blood
Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy for which there is an unmet need for novel treatment strategies. Here, we characterize the growth arrest and DNA damage-inducible gene gamma (GADD45g) as a novel tumor suppressor in AML. We show that GADD45g is preferentially silenced in AML, especially in AML with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations and mixed-lineage leukemia (MLL)-rearrangements, and reduced expression of GADD45g is correlated with poor prognosis in patients with AML. Upregulation of GADD45g impairs homologous recombination DNA repair, leading to DNA damage accumulation, and dramatically induces apoptosis, differentiation, and growth arrest and increases sensitivity of AML cells to chemotherapeutic drugs, without affecting normal cells. In addition, GADD45g is epigenetically silenced by histone deacetylation in AML, and its expression is further downregulated by oncogenes FLT3-ITD and MLL-AF9 in patients carrying these genetic abnormalities. Combination of the histone deacetylase 1/2 inhibitor romidepsin with the FLT3 tyrosine kinase inhibitor AC220 or the bromodomain inhibitor JQ1 exerts synergistic antileukemic effects on FLT3-ITD+ and MLL-AF9+ AML, respectively, by dually activating GADD45g. These findings uncover hitherto unreported evidence for the selective antileukemic role of GADD45g and provide novel strategies for the treatment of FLT3-ITD+ and MLL-AF9+ AML.
10.1182/blood.2020008229
Gadd45g initiates embryonic stem cell differentiation and inhibits breast cell carcinogenesis.
Zhang Xinbao,Li Yuting,Ji Junxiang,Wang Xin,Zhang Meng,Li Xiangfen,Zhang Yan,Zhu Zhenhua,Ye Shou-Dong,Wang Xiaoxiao
Cell death discovery
Many self-renewal-promoting factors of embryonic stem cells (ESCs) have been implicated in carcinogenesis, while little known about the genes that direct ESCs exit from pluripotency and regulate tumor development. Here, we show that the transcripts of Gadd45 family genes, including Gadd45a, Gadd45b, and Gadd45g, are gradually increased upon mouse ESC differentiation. Upregulation of Gadd45 members decreases cell proliferation and induces endodermal and trophectodermal lineages. In contrast, knockdown of Gadd45 genes can delay mouse ESC differentiation. Mechanistic studies reveal that Gadd45g activates MAPK signaling by increasing expression levels of the positive modulators of this pathway, such as Csf1r, Igf2, and Fgfr3. Therefore, inhibition of MAPK signaling with a MEK specific inhibitor is capable of eliminating the differentiation phenotype caused by Gadd45g upregulation. Meanwhile, GADD45G functions as a suppressor in human breast cancers. Enforced expression of GADD45G significantly inhibits tumor formation and breast cancer metastasis in mice through limitation of the propagation and invasion of breast cancer cells. These results not only expand our understanding of the regulatory network of ESCs, but also help people better treatment of cancers by manipulating the prodifferentiation candidates.
10.1038/s41420-021-00667-x
Gadd45 in Normal Hematopoiesis and Leukemia.
Advances in experimental medicine and biology
Gadd45a, Gadd45b, and Gadd45g have been implicated in cell cycle arrest, DNA repair, apoptosis, innate immunity, genomic stability, and modulation of normal blood cell development and leukemia. Each of the Gadd45 genes was shown to be regulated independently in myeloid cells in response to cytokine stimulation modulating blood cell survival and differentiation, including maintaining the quiescent stem cell pool. Gadd45a and Gadd45b were also shown to mediate the protective effects from UV in hematopoietic cells by separate signaling pathways involving either p38 activation or JNK inhibition. Furthermore, it was shown that gadd45a methylation in AML is predictive of poor survival. It was also shown that loss of Gadd45b accelerates the development of BCR-ABL driven CML in mice and leads to decreased median survival. The Gadd45b-deficient CML progenitors exhibited increased proliferation and decreased apoptosis, and this was associated with hyper-activation of c-Jun NH2-terminal kinase and Stat5. Moreover, loss of Gadd45a also accelerated the development of BCR-ABL driven CML, and this was associated with enhanced PI3K-AKT-mTOR-4E-BP1 signaling, upregulation of p30C/EBPα expression, and hyper-activation of p38 and Stat5. In human patients with chronic phase CML, gadd45a expression is up-regulated, whereas in accelerated and blast crisis phase patients, gadd45a is downregulated. Collectively, these results provide novel evidence that Gadd45a functions as a suppressor of BCR/ABL driven leukemia and may serve as a unique prognostic marker of CML progression. Thus Gadd45 proteins provide excellent targets for leukemia therapy.
10.1007/978-3-030-94804-7_3
Roles for GADD45 in Development and Cancer.
Advances in experimental medicine and biology
The Growth Arrest and DNA Damage-inducible 45 (GADD45) family of proteins are critical stress sensors that mediate various cellular responses, including DNA repair, cell cycle arrest, and apoptosis. Here, we review current literature investigating GADD45 family members as they relate to normal development and carcinogenesis. We first describe how modulation of GADD45 in model organisms has facilitated our understanding of roles for GADD45 family members in development and homeostasis. We then review current literature exploring roles for GADD45 in human cancer, describing cancer-associated alterations in expression of GADD45 family members; tumor suppressive and tumor promoting functions attributed to GADD5; and roles for GADD45 in cancer therapy. In exploring roles for GADD45 in development, homeostasis, and carcinogenesis, we aim to provide an informational resource that both highlighst current knowledge on this topic while also noting key gaps in our understanding of the biology of GADD45 that may be filled in order to best guide the development of novel approaches to improve diagnosis, monitoring, and therapy of human malignancies.
10.1007/978-3-030-94804-7_2
Analysis of long non-coding RNAs associated with disulfidptosis for prognostic signature and immunotherapy response in uterine corpus endometrial carcinoma.
Scientific reports
Disulfidptosis, the demise of cells caused by the abnormal breakdown of disulfide bonds and actin in the cytoprotein backbone, has attracted attention in studies concerning disulfide-related cell death and its potential implications in cancer treatment. This study utilized bioinformatics to detect disulfidptosis associated lncRNA prognostic markers (DALPMs) with Uterine Corpus Endometrial Carcinoma (UCEC)-related to investigate the correlation between these indicators and the tumor immune microenvironment. The RNA sequencing data and somatic mutation information of patients with UCEC were obtained from the Cancer Genome Atlas (TCGA) database. Patients were randomly divided into Train and Test groups. The findings revealed a potential prognostic model comprising 14 DALPMs. Both univariate and multivariate Cox analyses demonstrated that the model-derived risk score functioned as a standalone prognostic indicator for patients. Significant disparities in survival outcomes were observed between the high- and low-risk groups as defined by the model. Differences in tumor mutational burden (TMB), tumor immune dysfunction and exclusion (TIDE), and tumor microenvironment (TME) stromal cells between patients of the high- and low-risk groups were also observed. The forecast model comprising long non-coding RNAs (lncRNAs) associated with disulfidptosis can effectively anticipate patients' prognoses.
10.1038/s41598-023-49750-6
Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer.
Liu Xiaoguang,Olszewski Kellen,Zhang Yilei,Lim Esther W,Shi Jiejun,Zhang Xiaoshan,Zhang Jie,Lee Hyemin,Koppula Pranavi,Lei Guang,Zhuang Li,You M James,Fang Bingliang,Li Wei,Metallo Christian M,Poyurovsky Masha V,Gan Boyi
Nature cell biology
SLC7A11-mediated cystine uptake is critical for maintaining redox balance and cell survival. Here we show that this comes at a significant cost for cancer cells with high levels of SLC7A11. Actively importing cystine is potentially toxic due to its low solubility, forcing cancer cells with high levels of SLC7A11 (SLC7A11) to constitutively reduce cystine to the more soluble cysteine. This presents a significant drain on the cellular NADPH pool and renders such cells dependent on the pentose phosphate pathway. Limiting glucose supply to SLC7A11 cancer cells results in marked accumulation of intracellular cystine, redox system collapse and rapid cell death, which can be rescued by treatments that prevent disulfide accumulation. We further show that inhibitors of glucose transporters selectively kill SLC7A11 cancer cells and suppress SLC7A11 tumour growth. Our results identify a coupling between SLC7A11-associated cystine metabolism and the pentose phosphate pathway, and uncover an accompanying metabolic vulnerability for therapeutic targeting in SLC7A11 cancers.
10.1038/s41556-020-0496-x
Disulfidptosis: disulfide stress-induced cell death.
Trends in cell biology
The cystine transporter solute carrier family 7 member 11 (SLC7A11) (also known as xCT) promotes glutathione synthesis and counters oxidative stress-induced cell death, including ferroptosis, by importing cystine. Also, SLC7A11 plays a crucial role in tumor development. However, recent studies have uncovered an unexpected role of SLC7A11 in promoting disulfidptosis, a novel form of regulated cell death induced by disulfide stress. In this review, we examine the opposing roles of SLC7A11 in regulating redox homeostasis and cell survival/death, summarize current knowledge on disulfidptosis, and explore its potential in disease treatment. A deeper understanding of disulfidptosis will offer new insights into fundamental cellular homeostasis and facilitate the development of innovative therapies for disease treatment.
10.1016/j.tcb.2023.07.009
Impact of sweet, umami, and bitter taste receptor (TAS1R and TAS2R) genomic and expression alterations in solid tumors on survival.
Scientific reports
Originally identified on the tongue for their chemosensory role, the receptors for sweet, umami, and bitter taste are expressed in some cancers where they regulate important cellular processes including apoptosis and proliferation. We examined DNA mutations (n = 5103), structural variation (n = 7545), and expression (n = 6224) of genes encoding sweet or umami receptors (TAS1Rs) and bitter receptors (TAS2Rs) in 45 solid tumors subtypes compared to corresponding normal tissue using The Cancer Genome Atlas and the Genotype Tissue Expression Project databases. Expression of TAS1R and TAS2R genes differed between normal and cancer tissue, and nonsilent mutations occurred in many solid tumor taste receptor genes (~ 1-7%). Expression levels of certain TAS1Rs/TAS2Rs were associated with survival differences in 12 solid tumor subtypes. Increased TAS1R1 expression was associated with improved survival in lung adenocarcinoma (mean survival difference + 1185 days, p = 0.0191). Increased TAS2R14 expression was associated with worse survival in adrenocortical carcinoma (-1757 days, p < 0.001) and esophageal adenocarcinoma (-640 days, p = 0.0041), but improved survival in non-papillary bladder cancer (+ 343 days, p = 0.0436). Certain taste receptor genes may be associated with important oncologic pathways and could serve as biomarkers for disease outcomes.
10.1038/s41598-022-12788-z
PLTP is a p53 target gene with roles in cancer growth suppression and ferroptosis.
The Journal of biological chemistry
The tumor suppressor protein p53 suppresses cancer by regulating processes such as apoptosis, cell cycle arrest, senescence, and ferroptosis, which is an iron-mediated and lipid peroxide-induced cell death pathway. Whereas numerous p53 target genes have been identified, only a few appear to be critical for the suppression of tumor growth. Additionally, while ferroptosis is clearly implicated in tumor suppression by p53, few p53 target genes with roles in ferroptosis have been identified. We have previously studied germline missense p53 variants that are hypomorphic or display reduced activity. These hypomorphic variants are associated with increased risk for cancer, but they retain the majority of p53 transcriptional function; as such, study of the transcriptional targets of these hypomorphs has the potential to reveal the identity of other genes important for p53-mediated tumor suppression. Here, using RNA-seq in lymphoblastoid cell lines, we identify PLTP (phospholipid transfer protein) as a p53 target gene that shows impaired transactivation by three different cancer-associated p53 hypomorphs: P47S (Pro47Ser, rs1800371), Y107H (Tyr107His, rs368771578), and G334R (Gly334Arg, rs78378222). We show that enforced expression of PLTP potently suppresses colony formation in human tumor cell lines. We also demonstrate that PLTP regulates the sensitivity of cells to ferroptosis. Taken together, our findings reveal PLTP to be a p53 target gene that is extremely sensitive to p53 transcriptional function and which has roles in growth suppression and ferroptosis.
10.1016/j.jbc.2022.102637
Asparagine transport through SLC1A5/ASCT2 and SLC38A5/SNAT5 is essential for BCP-ALL cell survival and a potential therapeutic target.
British journal of haematology
B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) blasts strictly depend on the transport of extra-cellular asparagine (Asn), yielding a rationale for L-asparaginase (ASNase) therapy. However, the carriers used by ALL blasts for Asn transport have not been identified yet. Exploiting RS4;11 cells as BCP-ALL model, we have found that cell Asn is lowered by either silencing or inhibition of the transporters ASCT2 or SNAT5. The inhibitors V-9302 (for ASCT2) and GluγHA (for SNAT5) markedly lower cell proliferation and, when used together, suppress mTOR activity, induce autophagy and cause a severe nutritional stress, leading to a proliferative arrest and a massive cell death in both the ASNase-sensitive RS4;11 cells and the relatively ASNase-insensitive NALM-6 cells. The cytotoxic effect is not prevented by coculturing leukaemic cells with primary mesenchymal stromal cells. Leukaemic blasts of paediatric ALL patients express ASCT2 and SNAT5 at diagnosis and undergo marked cytotoxicity when exposed to the inhibitors. ASCT2 expression is positively correlated with the minimal residual disease at the end of the induction therapy. In conclusion, ASCT2 and SNAT5 are the carriers exploited by ALL cells to transport Asn, and ASCT2 expression is associated with a lower therapeutic response. ASCT2 may thus represent a novel therapeutic target in BCP-ALL.
10.1111/bjh.19516
Machine-learning based integrating bulk and single-cell RNA sequencing reveals the SLC38A5-CCL5 signaling as a promising target for clear cell renal cell carcinoma treatment.
Translational oncology
Cancer-associated fibroblasts paly critical roles in regulating cancer cell biological properties by intricate and dynamic communication networks. But the mechanism of CAFs in clear cell renal cell carcinoma (ccRCC) is not clear. In our study, we identified CAFs and malignant cells from the integrated scRNA-seq datasets and establish a CAF-derived communication signature based on the highly activated regulons ETS1 and MEF2C. We stratified the ccRCC TME into two molecular subtypes with distinct prognoses, immune cell infiltration landscapes, and immune-related characteristics. The model derived from signature demonstrated high accuracy and robustness in predicting prognosis and ICIs therapy responses. Subsequently, the SLC38A5 of the model was found upregulated in CAFs and was related to decreased survival probabilities, inflamed TME, and upregulated inhibitory checkpoints. SLC38A5 inhibition could attenuate the pro-tumoral abilities of CAFs in terms of proliferation, migration, and invasion. Mechanically, CCL5 could restore these properties induced by SLC38A5 inhibition. In conclusion, our communication signature and its derived model enabled a more precise selection of ccRCC patients who were potential beneficiaries of ICIs. Besides, the SLC38A5-CCL5 axis may serve as a promising target for ccRCC treatment.
10.1016/j.tranon.2023.101790
SLC38A5 promotes glutamine metabolism and inhibits cisplatin chemosensitivity in breast cancer.
Breast cancer (Tokyo, Japan)
BACKGROUND:Solute carrier family 38 member 5 (SLC38A5), as an amino acid transporter, play a vital role in cellular biological processes. In this study, we analyzed the function of SLC38A5 and its potential mechanism in breast cancer (BC) progression. METHODS:The expression of SLC38A5 in cancer and adjacent-normal tissues was analyzed by qRT-PCR and Western blot, and its correlation with patient prognosis was analyzed. The immunohistochemical staining of cancer tissues and adjacent-normal tissues was performed on SLC38A5-positive specimens. BC mice were successfully applied to examine the role of SLC38A5 on tumor proliferation using the CCK-8 assay. In BC cells and mouse tumor tissues, SLC38A5 and PCNA expression were determined by Western blotting. RESULTS:The study found that SLC38A5 was highly expressed in BC patients and associated with a poor survival. SLC38A5 silencing inhibited BC cell viability and glutamine uptake. In addition, SLC38A5 overexpression promoted BC cell viability via the glutamine metabolism. SLC38A5 inhibited cisplatin chemosensitivity in BC cells. Importantly, SLC38A5 silencing inhibited tumor growth in vivo. CONCLUSION:Our findings suggest that SLC38A5 enhances BC cell viability by glutamine metabolism, inhibits the chemical sensitivity of cisplatin in BC cells, and promotes tumor growth, emphasizing the clinical relevance of SLC38A5 in BC management as a novel potential therapeutic target.
10.1007/s12282-023-01516-8
Amino acid transporter SLC38A5 is a tumor promoter and a novel therapeutic target for pancreatic cancer.
Scientific reports
Pancreatic ductal adenocarcinoma (PDAC) cells have a great demand for nutrients in the form of sugars, amino acids, and lipids. Particularly, amino acids are critical for cancer growth and, as intermediates, connect glucose, lipid and nucleotide metabolism. PDAC cells meet these requirements by upregulating selective amino acid transporters. Here we show that SLC38A5 (SN2/SNAT5), a neutral amino acid transporter is highly upregulated and functional in PDAC cells. Using CRISPR/Cas9-mediated knockout of SLC38A5, we show its tumor promoting role in an in vitro cell line model as well as in a subcutaneous xenograft mouse model. Using metabolomics and RNA sequencing, we show significant reduction in many amino acid substrates of SLC38A5 as well as OXPHOS inactivation in response to SLC38A5 deletion. Experimental validation demonstrates inhibition of mTORC1, glycolysis and mitochondrial respiration in KO cells, suggesting a serious metabolic crisis associated with SLC38A5 deletion. Since many SLC38A5 substrates are activators of mTORC1 as well as TCA cycle intermediates/precursors, we speculate amino acid insufficiency as a possible link between SLC38A5 deletion and inactivation of mTORC1, glycolysis and mitochondrial respiration, and the underlying mechanism for PDAC attenuation. Overall, we show that SLC38A5 promotes PDAC, thereby identifying a novel, hitherto unknown, therapeutic target for PDAC.
10.1038/s41598-023-43983-1
SLC6A14 and SLC38A5 Drive the Glutaminolysis and Serine-Glycine-One-Carbon Pathways in Cancer.
Sniegowski Tyler,Korac Ksenija,Bhutia Yangzom D,Ganapathy Vadivel
Pharmaceuticals (Basel, Switzerland)
The glutaminolysis and serine-glycine-one-carbon pathways represent metabolic reactions that are reprogramed and upregulated in cancer; these pathways are involved in supporting the growth and proliferation of cancer cells. Glutaminolysis participates in the production of lactate, an oncometabolite, and also in anabolic reactions leading to the synthesis of fatty acids and cholesterol. The serine-glycine-one-carbon pathway is involved in the synthesis of purines and pyrimidines and the control of the epigenetic signature (DNA methylation, histone methylation) in cancer cells. Methionine is obligatory for most of the methyl-transfer reactions in the form of S-adenosylmethionine; here, too, the serine-glycine-one-carbon pathway is necessary for the resynthesis of methionine following the methyl-transfer reaction. Glutamine, serine, glycine, and methionine are obligatory to fuel these metabolic pathways. The first three amino acids can be synthesized endogenously to some extent, but the need for these amino acids in cancer cells is so high that they also have to be acquired from extracellular sources. Methionine is an essential amino acid, thus making it necessary for cancer cells to acquire this amino acid solely from the extracellular milieu. Cancer cells upregulate specific amino acid transporters to meet this increased demand for these four amino acids. SLC6A14 and SLC38A5 are the two transporters that are upregulated in a variety of cancers to mediate the influx of glutamine, serine, glycine, and methionine into cancer cells. SLC6A14 is a Na/Cl -coupled transporter for multiple amino acids, including these four amino acids. In contrast, SLC38A5 is a Na-coupled transporter with rather restricted specificity towards glutamine, serine, glycine, and methionine. Both transporters exhibit unique functional features that are ideal for the rapid proliferation of cancer cells. As such, these two amino acid transporters play a critical role in promoting the survival and growth of cancer cells and hence represent novel, hitherto largely unexplored, targets for cancer therapy.
10.3390/ph14030216