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Saudi Journal of Biological Sciences Jan 2024Epithelial cancer cells rely on the extracellular matrix (ECM) attachment in order to spread to other organs. Detachment from the ECM is necessary for these cells to...
Epithelial cancer cells rely on the extracellular matrix (ECM) attachment in order to spread to other organs. Detachment from the ECM is necessary for these cells to seed in other locations. When the attachment to the ECM is lost, cellular metabolism undergoes a significant shift from oxidative metabolism to glycolysis. Additionally, the cancer cells become more dependent on glutaminolysis to avoid a specific type of cell death known as anoikis, which is associated with ECM detachment. In our recent study, we observed increased expression of H3K27me3 demethylases, specifically KDM6A/B, in cancer cells that were resistant to anoikis. Since KDM6A/B is known to regulate cellular metabolism, we investigated the effects of suppressing KDM6A/B with GSK-J4 on the metabolic processes in these anoikis-resistant cancer cells. Our results from untargeted metabolomics revealed a profound impact of KDM6A/B inhibition on various metabolic pathways, including glycolysis, methyl histidine, spermine, and glutamate metabolism. Inhibition of KDM6A/B led to elevated reactive oxygen species (ROS) levels and depolarization of mitochondria, while reducing the levels of glutathione, an important antioxidant, by diminishing the intermediates of the glutamate pathway. Glutamate is crucial for maintaining a pool of reduced glutathione. Furthermore, we discovered that KDM6A/B regulates the key glycolytic genes expression like hexokinase, lactate dehydrogenase, and GLUT-1, which are essential for sustaining glycolysis in anoikis-resistant cancer cells. Overall, our findings demonstrated the critical role of KDM6A/B in maintaining glycolysis, glutamate metabolism, and glutathione levels. Inhibition of KDM6A/B disrupts these metabolic processes, leading to increased ROS levels and triggering cell death in anoikis-resistant cancer cells.
PubMed: 38107766
DOI: 10.1016/j.sjbs.2023.103871 -
BioRxiv : the Preprint Server For... Dec 2023Anoikis resistance or evasion of cell death triggered by cell detachment into suspension is a hallmark of cancer that is concurrent with cell survival and metastasis....
Anoikis resistance or evasion of cell death triggered by cell detachment into suspension is a hallmark of cancer that is concurrent with cell survival and metastasis. The effects of frequent matrix detachment encounters on the development of anoikis resistance in cancer remains poorly defined. Here we show using a panel of ovarian cancer models, that repeated exposure to suspension stress in vitro followed by attached recovery growth leads to the development of anoikis resistance paralleling in vivo development of anoikis resistance in ovarian cancer ascites. This resistance is concurrent with enhanced invasion, chemoresistance and the ability of anoikis adapted cells to metastasize to distant sites. Adapted anoikis resistant cells show a heightened dependency on oxidative phosphorylation and can also evade immune surveillance. We find that such acquired anoikis resistance is not genetic, as acquired resistance persists for a finite duration in the absence of suspension stress. Transcriptional reprogramming is however essential to this process, as acquisition of adaptive anoikis resistance in vitro and in vivo is exquisitely sensitive to inhibition of CDK8/19 Mediator kinase, a pleiotropic regulator of transcriptional reprogramming. Our data demonstrate that growth after recovery from repeated exposure to suspension stress is a direct contributor to metastasis and that inhibition of CDK8/19 Mediator kinase during such adaptation provides a therapeutic opportunity to prevent both local and distant metastasis in cancer.
PubMed: 38106208
DOI: 10.1101/2023.12.04.569970 -
Nature Communications Dec 2023DNA methylation at the fifth position of cytosine (5-methylcytosine, 5mC) is a crucial epigenetic modification for regulating gene expression, but little is known about...
DNA methylation at the fifth position of cytosine (5-methylcytosine, 5mC) is a crucial epigenetic modification for regulating gene expression, but little is known about how it regulates gene expression in insects. Here, we pursue the detailed molecular mechanism by which DNMT1-mediated 5mC maintenance regulates female reproduction in the German cockroach, Blattella germanica. Our results show that Dnmt1 knockdown decreases the level of 5mC in the ovary, upregulating numerous genes during choriogenesis, especially the transcription factor ftz-f1. The hypomethylation at the ftz-f1 promoter region increases and prolongs ftz-f1 expression in ovarian follicle cells during choriogenesis, which consequently causes aberrantly high levels of 20-hydroxyecdysone and excessively upregulates the extracellular matrix remodeling gene Mmp1. These changes further impair choriogenesis and disrupt fertilization by causing anoikis of the follicle cells, a shortage of chorion proteins, and malformation of the sponge-like bodies. This study significantly advances our understanding of how DNA 5mC modification regulates female reproduction in insects.
Topics: Animals; Female; DNA-Binding Proteins; Transcription Factors; Gene Expression Regulation; Insecta; Fertilization
PubMed: 38086980
DOI: 10.1038/s41467-023-43987-5 -
Development (Cambridge, England) Dec 2023To investigate the role of the nuclear receptor NR5A1 in the testis after sex determination, we analyzed mice lacking NR5A1 in Sertoli cells (SCs) from embryonic day (E)...
To investigate the role of the nuclear receptor NR5A1 in the testis after sex determination, we analyzed mice lacking NR5A1 in Sertoli cells (SCs) from embryonic day (E) 13.5 onwards. Ablation of Nr5a1 impaired the expression of genes characteristic of SC identity (e.g. Sox9 and Amh), caused SC death from E14.5 onwards through a Trp53-independent mechanism related to anoikis, and induced disorganization of the testis cords. Together, these effects caused germ cells to enter meiosis and die. Single-cell RNA-sequencing experiments revealed that NR5A1-deficient SCs changed their molecular identity: some acquired a 'pre-granulosa-like' cell identity, whereas other reverted to a 'supporting progenitor-like' cell identity, most of them being 'intersex' because they expressed both testicular and ovarian genes. Fetal Leydig cells (LCs) did not display significant changes, indicating that SCs are not required beyond E14.5 for their emergence or maintenance. In contrast, adult LCs were absent from postnatal testes. In addition, adult mutant males displayed persistence of Müllerian duct derivatives, decreased anogenital distance and reduced penis length, which could be explained by the loss of AMH and testosterone synthesis due to SC failure.
Topics: Animals; Male; Mice; Anoikis; Cell Death; Sertoli Cells; Testis
PubMed: 38078651
DOI: 10.1242/dev.201710 -
Frontiers in Bioscience (Landmark... Nov 2023Cervical cancer has high morbidity and intratumor heterogeneity. Anoikis, a form of programmed cell death preventing detached cancer cells from readhering, may serve as...
BACKGROUND
Cervical cancer has high morbidity and intratumor heterogeneity. Anoikis, a form of programmed cell death preventing detached cancer cells from readhering, may serve as a potential prognostic signature for cervical cancer. This study aimed to assess the predictive performance of anoikis patterns in cervical cancer prognosis.
METHODS
Differentially expressed anoikis-related genes (DEARGs) were identified between normal and cancer samples using data from the Gene Expression Omnibus database with the elucidation of mutation status and bio-function. Novel anoikis molecular subtypes were defined in The Cancer Genome Atlas (TCGA) cohort with consensus clustering analysis. A multigene prognostic signature was constructed through least absolute shrinkage and selection operator (LASSO) Cox analysis with internal and external validation. The nomogram-based survival probability of cervical cancer over 3 and 5 years was predicted and assessed with calibration, receiver operating characteristic, decision curve analysis, and Kaplan-Meier curves. Additionally, mutation, function, and immune analysis were conducted among different risk groups.
RESULTS
We identified 77 DEARGs between normal and cervical cancer tissues and explored their mutation status and functions. The TCGA cohort could be categorized into two subtypes based on these genes. Furthermore, seven prognostic signature genes were constructed, and the nomogram involving DEARGs and clinicopathological characteristics showed satisfactory predictive performance. Functional analysis indicated that immune-related genes were enriched, and immune status, as well as sensitivity of chemotherapies and targeting drugs, were correlated with the risk model.
CONCLUSIONS
Anoikis patterns play important roles in tumor immunity and can be used to predict the prognosis of cervical cancers.
Topics: Humans; Female; Uterine Cervical Neoplasms; Anoikis; Drug Delivery Systems; Immunity
PubMed: 38062824
DOI: 10.31083/j.fbl2811287 -
Heliyon Nov 2023Qizhu Anti-Cancer Recipe (QACR) is a traditional Chinese medicine widely used in treating several liver diseases. However, its function and the relevant mechanism...
BACKGROUND
Qizhu Anti-Cancer Recipe (QACR) is a traditional Chinese medicine widely used in treating several liver diseases. However, its function and the relevant mechanism underlying its effect in treating hepatocellular carcinoma (HCC) remain unknown. The aim of this study was to explore the effect of QACR in HCC, which are expected to be a potential therapeutic scheme for HCC.
MATERIALS AND METHODS
The chemical compositions of QACR were determined by liquid chromatography/quadrupole time-of-fight mass spectrometry (LC-QTOF-MS). The anoikis-resistant HCC cell proliferation and angiopoiesis were detected using the cell counting kit 8 (CCK8) assay, trypan blue, calcein AM/EthD-1, flow cytometer, Western blot, and tube formation assays. An orthotopic xenograft mouse model was established to evaluate the effects of the QACR. The expression of proliferating cell nuclear antigen (PCNA), Bcl-2, CD31, caspase-3, caspase-8, caspase-9, PARP-1, DFF40, phospho--Jun NH2-terminal kinase (-JNK), and JNK was assessed using Western blot and immunohistochemical analysis.
RESULTS
QACR reduced the growth and tube formation of anoikis-resistant HCC cells and enhanced cell apoptosis . In the orthotopic xenograft mouse models, QACR suppressed the tumorigenesis of HCC . Mechanistically, QACR modulated the JNK pathway. The JNK inhibitor (SP600125) reverses the inhibitory effects of QACR on anoikis-resistant HCC cell proliferation and angiopoiesis.
CONCLUSION
Our study suggests that QACR suppresses the proliferation and angiopoiesis of anoikis-resistant HCC cells by activating the JNK pathway. Therefore, QACR is a promising new therapeutic strategy for treating hepatocellular carcinoma.
PubMed: 38053871
DOI: 10.1016/j.heliyon.2023.e22089 -
Heliyon Nov 2023Anoikis-related long non-coding RNAs (ARLs) play a critical role in tumor metastasis and progression, suggesting that they may serve as risk markers for cancer. This...
BACKGROUND
Anoikis-related long non-coding RNAs (ARLs) play a critical role in tumor metastasis and progression, suggesting that they may serve as risk markers for cancer. This study aimed to investigate the prognostic value of ARLs in patients with lung adenocarcinoma (LUAD).
METHODS
Clinical data, RNA sequencing (RNA-seq) data, and mutation data from the LUAD project were obtained from The Cancer Genome Atlas (TCGA) database. The Molecular Signatures Database (MSigDB) and the GeneCard database were used to collect an anoikis-related gene (ARG) set. Pearson correlation analysis was performed to identify ARLs. LASSO and Cox regression were then used to establish a prognostic risk signature for ARLs. The median risk score served as the basis for categorizing patients into high and low-risk groups. Kaplan-Meier analysis was utilized to compare the prognosis between these two groups. The study also examined the associations between risk scores and prognosis, clinicopathological characteristics, immune status, tumor mutation burden (TMB), and chemotherapeutic agents. LncRNA expression was assessed using quantitative real-time PCR (qRT-PCR).
RESULTS
A total of 480 RNA expression profiles, 501 ARGs, and 2698 ARLs were obtained from the database. A prognostic ARL signature for LUAD was established, consisting of 9 lncRNAs. Patients in the low-risk group exhibited significantly better prognosis compared to those in the high-risk group ( < 0.001). The 9 lncRNAs from the ARL signature were identified as independent prognostic factors ( < 0.001). The signature demonstrated high accuracy in predicting LUAD prognosis, with area under the curve values exceeding 0.7. The risk scores for ARLs showed strong negative correlations with stroma score ( = 5.9E-07, R = -0.23), immune score ( = 9.7E-09, R = -0.26), and microenvironment score ( = 8E-11, R = -0.29). Additionally, the low-risk group exhibited significantly higher TMB compared to the high-risk group ( = 4.6E-05). High-risk status was significantly associated with lower half-maximal inhibitory concentrations for most chemotherapeutic drugs.
CONCLUSION
This newly constructed signature based on nine ARLs is a useful instrument for the risk stratification of LUAD patients. The signature has potential clinical significance for predicting the prognosis of LUAD patients and guiding personalized immunotherapy.
PubMed: 38053861
DOI: 10.1016/j.heliyon.2023.e22200 -
BMC Urology Dec 2023The prevalence of bladder urothelial carcinoma (BLCA) is significant on a global scale. Anoikis is a type of procedural cell death that has an important role in tumor...
BACKGROUND
The prevalence of bladder urothelial carcinoma (BLCA) is significant on a global scale. Anoikis is a type of procedural cell death that has an important role in tumor invasion and metastasis. The advent of single-cell RNA sequencing (scRNA-seq) approaches has revolutionized the genomics field by providing unprecedented opportunities for elucidating cellular heterogeneity. Understanding the mechanisms associated with anoikis in BLCA is essential to improve its survival rate.
METHODS
Data on BLCA and clinical information were acquired from the databases of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). ARGs were obtained from Genecards and Harmonizome databases. According to univariate Cox regression analysis, the least absolute shrinkage and selection operator (LASSO) algorithm was utilized to select the ARGs associated with the overall rate (OS). A multivariate Cox regression analysis was carried out to identify eight prognostic ARGs, leading to the establishment of a risk model. The OS rate of BLCA patients was evaluated using Kaplan-Meier survival analysis. To explore the molecular mechanism in low- and high-risk groups, we employed Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSVA). Immune infiltration landscape estimation was performed using ESTIMATE, CIBERSOT, and single sample gene set enrichment analysis (ssGSEA) algorithms. Patients were categorized into different subgroups through consensus clustering analysis. We employed biological functional enrichment analysis and conducted immune infiltration analysis to examine the disparities in potential biological functions, infiltration of immune cells, immune activities, and responses to immunotherapy.
RESULTS
We identified 647 ARGs and 37 survival-related genes. We further developed a risk scoring model to quantitatively assess the predictive capacity of ARGs. The high-risk score group exhibited an unfavorable prognosis, whereas the low-risk score group demonstrated a converse effect. We also found that the two groups of patients might respond differently to immune targets and anti-tumor drugs.
CONCLUSION
The nomogram with 8 ARGs may help guide treatment of BLCA. The systematic assessment of risk scores can help to design more individualized and precise treatment strategies for BLCA patients.
Topics: Humans; Prognosis; Anoikis; Carcinoma, Transitional Cell; Urinary Bladder Neoplasms; Nomograms
PubMed: 38049825
DOI: 10.1186/s12894-023-01382-8 -
Frontiers in Molecular Biosciences 2023To investigate the potential association between Anoikis-related genes, which are responsible for preventing abnormal cellular proliferation, and rheumatoid arthritis...
To investigate the potential association between Anoikis-related genes, which are responsible for preventing abnormal cellular proliferation, and rheumatoid arthritis (RA). Datasets GSE89408, GSE198520, and GSE97165 were obtained from the GEO with 282 RA patients and 28 healthy controls. We performed differential analysis of all genes and genes. We performed a protein-protein interaction network analysis and identified hub genes based on and cytoscape. Consistent clustering was performed with subgrouping of the disease. SsGSEA were used to calculate immune cell infiltration. Spearman's correlation analysis was employed to identify correlations. Enrichment scores of the GO and KEGG were calculated with the ssGSEA algorithm. The WGCNA and the database were used to mine hub genes' interactions with drugs. There were 26 differentially expressed Anoikis-related genes ( = 0.05, log2FC = 1) and HLA genes exhibited differential expression ( < 0.05) between the disease and control groups. Protein-protein interaction was observed among differentially expressed genes, and the correlation between and was found to be the highest; There were significant differences in the degree of immune cell infiltration between most of the immune cell types in the disease group and normal controls ( < 0.05). Anoikis-related genes were highly correlated with HLA genes. Based on the expression of Anoikis-related genes, RA patients were divided into two disease subtypes (cluster1 and cluster2). There were 59 differentially expressed Anoikis-related genes found, which exhibited significant differences in functional enrichment, immune cell infiltration degree, and gene expression ( < 0.05). Cluster2 had significantly higher levels in all aspects than cluster1 did. The co-expression network analysis showed that cluster1 had 51 hub differentially expressed genes and cluster2 had 72 hub differentially expressed genes. Among them, three hub genes of cluster1 were interconnected with 187 drugs, and five hub genes of cluster2 were interconnected with 57 drugs. Our study identified a link between Anoikis-related genes and RA, and two distinct subtypes of RA were determined based on Anoikis-related gene expression. Notably, cluster2 may represent a more severe state of RA.
PubMed: 38046810
DOI: 10.3389/fmolb.2023.1202371 -
Advanced Science (Weinheim,... Feb 2024Cells constantly sense and respond to not only biochemical but also biomechanical changes in their microenvironment, demanding for dynamic metabolic adaptation. ECM...
Cells constantly sense and respond to not only biochemical but also biomechanical changes in their microenvironment, demanding for dynamic metabolic adaptation. ECM stiffening is a hallmark of cancer aggressiveness, while survival under substrate detachment also associates with poor prognosis. Mechanisms underlying this, non-linear mechano-response of tumor cells may reveal potential double-hit targets for cancers. Here, an integrin-GSK3β-FTO-mTOR axis is reported, that can integrate stiffness sensing to ensure both the growth advantage endowed by rigid substrate and cell death resistance under matrix detachment. It is demonstrated that substrate stiffening can activate mTORC1 and elevate mTOR level through integrins and GSK3β-FTO mediated mRNA m A modification, promoting anabolic metabolism. Inhibition of this axis upon ECM detachment enhances autophagy, which in turn conveys resilience of tumor cells to anoikis, as it is demonstrated in human breast ductal carcinoma in situ (DCIS) and mice malignant ascites. Collectively, these results highlight the biphasic mechano-regulation of cellular metabolism, with implications in tumor growth under stiffened conditions such as fibrosis, as well as in anoikis-resistance during cancer metastasis.
Topics: Humans; Animals; Mice; Mechanistic Target of Rapamycin Complex 1; Anoikis; Signal Transduction; Glycogen Synthase Kinase 3 beta; TOR Serine-Threonine Kinases; Neoplasms; Integrins; Tumor Microenvironment; Alpha-Ketoglutarate-Dependent Dioxygenase FTO
PubMed: 38041494
DOI: 10.1002/advs.202307206