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Autophagy Jul 2024Macroautophagy/autophagy-mediated anoikis resistance is crucial for tumor metastasis. As a key autophagy-related protein, ATG4B has been demonstrated to be a prospective...
Macroautophagy/autophagy-mediated anoikis resistance is crucial for tumor metastasis. As a key autophagy-related protein, ATG4B has been demonstrated to be a prospective anti-tumor target. However, the existing ATG4B inhibitors are still far from clinical application, especially for tumor metastasis. In this study, we identified a novel circRNA, circSPECC1, that interacted with ATG4B. CircSPECC1 facilitated liquid-liquid phase separation of ATG4B, which boosted the ubiquitination and degradation of ATG4B in gastric cancer (GC) cells. Thus, pharmacological addition of circSPECC1 may serve as an innovative approach to suppress autophagy by targeting ATG4B. Specifically, the circSPECC1 underwent significant mA modification in GC cells and was subsequently recognized and suppressed by the mA reader protein ELAVL1/HuR. The activation of the ELAVL1-circSPECC1-ATG4B pathway was demonstrated to mediate anoikis resistance in GC cells. Moreover, we also verified that the above pathway was closely related to metastasis in tissues from GC patients. Furthermore, we determined that the FDA-approved compound lopinavir efficiently enhanced anoikis and prevented metastasis by eliminating repression of ELAVL1 on circSPECC1. In summary, this study provides novel insights into ATG4B-mediated autophagy and introduces a viable clinical inhibitor of autophagy, which may be beneficial for the treatment of GC with metastasis.
Topics: Anoikis; Autophagy; Humans; RNA, Circular; Cell Line, Tumor; Cysteine Endopeptidases; Lopinavir; Stomach Neoplasms; Autophagy-Related Proteins; Animals; Mice; Ubiquitination
PubMed: 38433354
DOI: 10.1080/15548627.2024.2325304 -
Journal of Experimental & Clinical... Oct 2023Epstein-Barr virus (EBV) is the first discovered human tumor virus that is associated with a variety of malignancies of both lymphoid and epithelial origin including...
Anoikis resistance and immune escape mediated by Epstein-Barr virus-encoded latent membrane protein 1-induced stabilization of PGC-1α promotes invasion and metastasis of nasopharyngeal carcinoma.
BACKGROUND
Epstein-Barr virus (EBV) is the first discovered human tumor virus that is associated with a variety of malignancies of both lymphoid and epithelial origin including nasopharyngeal carcinoma (NPC). The EBV-encoded latent membrane protein 1 (LMP1) has been well-defined as a potent oncogenic protein, which is intimately correlated with NPC pathogenesis. Anoikis is considered to be a physiological barrier to metastasis, and avoiding anoikis is a major hallmark of metastasis. However, the role of LMP1 in anoikis-resistance and metastasis of NPC has not been fully identified.
METHODS
Trypan blue staining, colony formation assay, flow cytometry, and TUNEL staining, as well as the detection of apoptosis and anoikis resistance-related markers was applied to evaluate the anoikis-resistant capability of NPC cells cultured in ultra-low adhesion condition. Co-immunoprecipitation (Co-IP) experiment was performed to determine the interaction among LMP1, PRMT1 and PGC-1α. Ex vivo ubiquitination assay was used to detect the ubiquitination level of PGC-1α. Anoikis- resistant LMP1-positive NPC cell lines were established and applied for the xenograft and metastatic animal experiments.
RESULTS
Our current findings reveal the role of LMP1-stabilized peroxisome proliferator activated receptor coactivator-1a (PGC-1α) in anoikis resistance and immune escape to support the invasion and metastasis of NPC. Mechanistically, LMP1 enhances PGC-1α protein stability by promoting the interaction between arginine methyltransferase 1 (PRMT1) and PGC-1α to elevate the methylation modification of PGC-1α, thus endowing NPC cells with anoikis-resistance. Meanwhile, PGC-1α mediates the immune escape induced by LMP1 by coactivating with STAT3 to transcriptionally up-regulate PD-L1 expression.
CONCLUSION
Our work provides insights into how virus-encoded proteins recruit and interact with host regulatory elements to facilitate the malignant progression of NPC. Therefore, targeting PGC-1α or PRMT1-PGC-1α interaction might be exploited for therapeutic gain for EBV-associated malignancies.
Topics: Animals; Humans; Nasopharyngeal Carcinoma; Herpesvirus 4, Human; Anoikis; Nasopharyngeal Neoplasms; Carcinoma; Epstein-Barr Virus Infections; Membrane Proteins; Viral Matrix Proteins; Cell Line, Tumor; Protein-Arginine N-Methyltransferases; Repressor Proteins
PubMed: 37803433
DOI: 10.1186/s13046-023-02835-6 -
Frontiers in Immunology 2023Anoikis is a programmed cell death process that was proven to be associated with cancer. Uroepithelial carcinoma of the bladder (BLCA) is a malignant disease of the...
BACKGROUND
Anoikis is a programmed cell death process that was proven to be associated with cancer. Uroepithelial carcinoma of the bladder (BLCA) is a malignant disease of the urinary tract and has a strong metastatic potential. To determine whether anoikis-associated genes can predict the prognosis of BLCA accurately, we evaluated the prognostic value of anoikis-associated genes in BLCA and constructed the best model to predict prognosis.
METHOD
The BLCA transcriptome data were downloaded from TCGA and GEO databases, and genes with differential expression were selected and then clustered using non-negative matrix factorization (NMF). The genes with the most correlation with anoikis were screened and identified using univariate Cox regression, lasso regression, and multivariate Cox regression. The GEO dataset was used for external validation. Nomograms were created based on risk characteristics in combination with clinical variants and the performance of the model was validated with receiver operating characteristic (ROC) curves. The immunotherapeutic significance of this risk score was assessed using the immune phenomenon score (IPS). IC50 values of predictive chemotherapeutic agents were calculated. Finally, we used RT-qPCR to determine the mRNA expression of four genes, , , , and .
RESULT
We screened 406 tumor samples and 19 normal tissue samples from the TCGA database. Based on anoikis-associated genes, we classified patients into two subtypes (C1 and C2) using NMF method. Subsequently, nine core genes were screened by multiple methods after analysis, which were used to construct risk profiles. The design of nomograms based on risk profiles and clinical variables, ROC, and calibration curves confirmed that the model could well have the ability to predict the survival of BLCA patients at 1, 3, and 5 years. By predicting the IC50 values of chemotherapeutic drugs, it was learned that the high-risk group (HRG) was more susceptible to paclitaxel, gemcitabine, and cisplatin, and the low-risk group (LRG) was more susceptible to veriparib and afatinib.
CONCLUSION
In summary, the risk score of anoikis-associated genes can be applied as a predictor to predict the prognosis of BLCA in clinical practice.
Topics: Humans; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Urinary Bladder; Anoikis; Genes, cdc
PubMed: 37275895
DOI: 10.3389/fimmu.2023.1122570 -
Molecular Therapy. Nucleic Acids Jun 2021Viral infections lead to the death of more than a million people each year around the world, both directly and indirectly. Viruses interfere with many cell functions,... (Review)
Review
Viral infections lead to the death of more than a million people each year around the world, both directly and indirectly. Viruses interfere with many cell functions, particularly critical pathways for cell death, by affecting various intracellular mediators. MicroRNAs (miRNAs) are a major example of these mediators because they are involved in many (if not most) cellular mechanisms. Virus-regulated miRNAs have been implicated in three cell death pathways, namely, apoptosis, autophagy, and anoikis. Several molecules (e.g., BECN1 and B cell lymphoma 2 [BCL2] family members) are involved in both apoptosis and autophagy, while activation of anoikis leads to cell death similar to apoptosis. These mechanistic similarities suggest that common regulators, including some miRNAs (e.g., miR-21 and miR-192), are involved in different cell death pathways. Because the balance between cell proliferation and cell death is pivotal to the homeostasis of the human body, miRNAs that regulate cell death pathways have drawn much attention from researchers. miR-21 is regulated by several viruses and can affect both apoptosis and anoikis via modulating various targets, such as PDCD4, PTEN, interleukin (IL)-12, Maspin, and Fas-L. miR-34 can be downregulated by viral infection and has different effects on apoptosis, depending on the type of virus and/or host cell. The present review summarizes the existing knowledge on virus-regulated miRNAs involved in the modulation of cell death pathways. Understanding the mechanisms for virus-mediated regulation of cell death pathways could provide valuable information to improve the diagnosis and treatment of many viral diseases.
PubMed: 33898103
DOI: 10.1016/j.omtn.2021.03.011 -
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 -
Cell Biology International Apr 2023The development of effective treatments for cancers requires investigations for a more detailed and comprehensive understanding of the basic cellular mechanisms... (Review)
Review
The development of effective treatments for cancers requires investigations for a more detailed and comprehensive understanding of the basic cellular mechanisms involved in carcinogenesis, cancer progression, and metastasis. One of those driving mechanisms is anoikis, a special type of apoptosis, which is induced by losing anchorage from the extracellular matrix (ECM). In other words, resisting death in detached cells (cells without ECM) forms an anoikis-resistant phenotype. Since the anoikis-resistance state compensates for the initial steps of cancer metastasis, this review aimed to discuss mechanisms of gaining anoikis/anoikis resistance phenotype in tumor cells. Finally, we highlighted the significance of anoikis in malignancies so as to provide clear insight into cancer diagnosis and therapy development.
Topics: Humans; Anoikis; Signal Transduction; Neoplasms; Neoplasm Metastasis; Cell Line, Tumor
PubMed: 36453448
DOI: 10.1002/cbin.11970 -
Frontiers in Endocrinology 2023Prostate cancer is one of the most common malignancies in males wherein 1 in 8 men are diagnosed with this disease in their lifetime. The urgency to find novel... (Review)
Review
Prostate cancer is one of the most common malignancies in males wherein 1 in 8 men are diagnosed with this disease in their lifetime. The urgency to find novel therapeutic interventions is associated with high treatment resistance and mortality rates associated with castration-resistant prostate cancer. Anoikis is an apoptotic phenomenon for normal epithelial or endothelial cells that have lost their attachment to the extracellular matrix (ECM). Tumor cells that lose their connection to the ECM can die via apoptosis or survive via anoikis resistance and thus escaping to distant organs for metastatic progression. This review discusses the recent advances made in our understanding of the signaling effectors of anoikis in prostate cancer and the approaches to translate these mechanistic insights into therapeutic benefits for reducing lethal disease outcomes (by overcoming anoikis resistance). The prostate tumor microenvironment is a highly dynamic landscape wherein the balance between androgen signaling, cell lineage changes, epithelial-mesenchymal transition (EMT), extracellular matrix interactions, actin cytoskeleton remodeling as well as metabolic changes, confer anoikis resistance and metastatic spread. Thus, these mechanisms also offer unique molecular treatment signatures, exploitation of which can prime prostate tumors to anoikis induction with a high translational significance.
Topics: Male; Humans; Anoikis; Prostate; Tumor Microenvironment; Endothelial Cells; Prostatic Neoplasms
PubMed: 37091854
DOI: 10.3389/fendo.2023.1160267 -
Biochemical and Biophysical Research... Sep 2023The prognostic value of anoikis in NSCLC and its mechanism in tumorigenesis and progress have not been fully elucidated. This study aimed to reveal the correlation...
The prognostic value of anoikis in NSCLC and its mechanism in tumorigenesis and progress have not been fully elucidated. This study aimed to reveal the correlation between anoikis-related genes (ARGs) and tumor prognosis, to reveal molecular and immune features, and to evaluate the anticancer drug sensitivity and the efficacy of immunotherapy of NSCLC. ARGs were selected from both the GeneCards and Harmonizome databases and then were intersected with the Cancer Genome Atlas (TCGA) database by differential expression analysis, followed by functional analysis of the target ARGs. An ARGs-based prognostic signature was constructed using LASSO (least absolute shrinkage and selection operator) Cox regression analysis; Kaplan-Meier analysis, univariant and multivariant Cox analysis were used to validate the value of this model in NSCLC prognosis. Differential analyses on molecular and immune landscapes were applied in the model. Anticancer drug sensitivity and efficacy in immune-checkpoint inhibitors (ICI) therapy were analyzed. A total of 509 ARGs and 168 differentially expressed ARGs in NSCLC were generated. Functional analysis revealed enrichment in extracolonic apoptotic signaling pathway, collagen-containing ECM, and integrin binding, and indicated an association with the PI3K-Akt signaling pathway. Subsequently, a 14-genes signature was generated. The high-risk group had a worse prognosis, with higherM0 and M2 macrophage infiltration, and fewer CD8 T-cells and T follicular helper (TFH) cells. The high-risk group had higher expression of immune checkpoint genes, HLA-I genes, and higher TIDE scores than the low-risk group, leading to less benefit of ICI therapy. Additionally, an Immunohistochemical staining comparison revealed that FADD was highly expressed in tumor tissue, compared to normal tissue, consistent with the previous results.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Anoikis; Phosphatidylinositol 3-Kinases; Lung Neoplasms; Immune Checkpoint Inhibitors
PubMed: 37385008
DOI: 10.1016/j.bbrc.2023.06.049 -
Oncogene Sep 2021Anoikis is a type of programmed cell death induced by loss of anchorage to the extracellular matrix (ECM). Anoikis resistance (AR) is crucial for the survival of...
Anoikis is a type of programmed cell death induced by loss of anchorage to the extracellular matrix (ECM). Anoikis resistance (AR) is crucial for the survival of metastatic cancer cells in blood, lymphatic circulation and distant organs. Compared to ordinary cancer cells, anoikis resistant cancer cells undergo various cellular and molecular alterations, probably characterizing the cells with unique features not limited to anoikis resistance. However, the molecular mechanisms connecting anoikis resistance to other metastatic properties are still poorly understood. Here, the biological interaction between anoikis resistance and angiogenesis as well as their involvement into peritoneal metastasis of gastric cancer (GC) were investigated in vitro and in vivo. The prognostic value of key components involved in this interaction was evaluated in the GC cohort. Compared to ordinary GC cells, GC cells exhibited stronger metastatic and pro-angiogenic traits corresponding to elevated PDGFB secretion. Mechanistically, transcription factor C/EBPβ facilitated PDGFB transcription by directly binding to and interacting with PDGFB promoter elements, subsequently increasing PDGFB secretion. Secreted PDGFB promoted the survival of detached GC cells through a C/EBPβ-dependent self-feedback loop. Moreover, secreted PDGFB promoted angiogenesis in metastases via activation of the MAPK/ERK signaling pathway in vascular endothelial cells. Both C/EBPβ activation level and PDGFB expression were significantly elevated in GC and correlated with metastatic progression and poor prognosis of patients with GC. Overall, interaction between GC cells and vascular endothelial cells promotes angiogenesis and peritoneal metastasis of GC based on C/EBPβ-mediated PDGFB autocrine and paracrine signaling. C/EBPβ-PDGFB-PDGFRβ-MAPK axis promises to be potential prognostic biomarkers and therapeutic targets for peritoneal metastasis of GC.
Topics: Animals; Anoikis; Autocrine Communication; CCAAT-Enhancer-Binding Protein-beta; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Mice; Neoplasm Transplantation; Paracrine Communication; Peritoneal Neoplasms; Prognosis; Promoter Regions, Genetic; Proto-Oncogene Proteins c-sis; Stomach Neoplasms; Up-Regulation
PubMed: 34341514
DOI: 10.1038/s41388-021-01988-y -
Advances in Medical Sciences Sep 2023Programmed cell death plays a crucial role in maintaining the homeostasis and integrity of multicellular organisms, and its dysregulation contributes to the pathogenesis... (Review)
Review
Programmed cell death plays a crucial role in maintaining the homeostasis and integrity of multicellular organisms, and its dysregulation contributes to the pathogenesis of many diseases. Programmed cell death is regulated by a range of macromolecules and low-molecular messengers, including ceramides. Endogenous ceramides have different functions, that are influenced by their localization and the presence of their target molecules. This article provides an overview of the current understanding of ceramides and their impact on various types of programmed cell death, including apoptosis, anoikis, macroautophagy and mitophagy, and necroptosis. Moreover, it highlights the emergence of dihydroceramides as a new class of bioactive sphingolipids and their downstream targets as well as their future roles in cancer cell growth, drug resistance and tumor metastasis.
Topics: Ceramides; Apoptosis; Sphingolipids; Homeostasis
PubMed: 37866204
DOI: 10.1016/j.advms.2023.10.004