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1.
Int J Mol Sci ; 25(11)2024 May 21.
Article in English | MEDLINE | ID: mdl-38891761

ABSTRACT

Abiraterone acetate (AA) serves as a medication for managing persistent testosterone production in patients with metastatic castration-resistant prostate cancer (mCRPC). However, its efficacy varies among individuals; thus, the identification of biomarkers to predict and follow treatment response is required. In this pilot study, we explored the potential of circulating microRNAs (c-miRNAs) to stratify patients based on their responsiveness to AA. We conducted an analysis of plasma samples obtained from a cohort of 33 mCRPC patients before and after three, six, and nine months of AA treatment. Using miRNA RT-qPCR panels for candidate discovery and TaqMan RT-qPCR for validation, we identified promising miRNA signatures. Our investigation indicated that a signature based on miR-103a-3p and miR-378a-5p effectively discriminates between non-responder and responder patients, while also following the drug's efficacy over time. Additionally, through in silico analysis, we identified target genes and transcription factors of the two miRNAs, including PTEN and HOXB13, which are known to play roles in AA resistance in mCRPC. In summary, our study highlights two c-miRNAs as potential companion diagnostics of AA in mCRPC patients, offering novel insights for informed decision-making in the treatment of mCRPC.


Subject(s)
Abiraterone Acetate , Biomarkers, Tumor , MicroRNAs , Prostatic Neoplasms, Castration-Resistant , Humans , Male , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/blood , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/pathology , Prostatic Neoplasms, Castration-Resistant/diagnosis , Abiraterone Acetate/therapeutic use , Pilot Projects , Aged , MicroRNAs/blood , MicroRNAs/genetics , Biomarkers, Tumor/blood , Biomarkers, Tumor/genetics , Middle Aged , Gene Expression Regulation, Neoplastic/drug effects , PTEN Phosphohydrolase/genetics , Circulating MicroRNA/blood , Neoplasm Metastasis , Homeodomain Proteins/genetics , Homeodomain Proteins/blood , Aged, 80 and over
2.
Int J Mol Sci ; 25(11)2024 May 27.
Article in English | MEDLINE | ID: mdl-38891994

ABSTRACT

The PI3K/AKT pathway plays a pivotal role in cellular processes, and its dysregulation is implicated in various cancers, including colorectal cancer. The present study correlates the expression levels of critical genes (PIK3CA, PTEN, AKT1, FOXO1, and FRAP) in 60 tumor tissues with clinicopathological and demographic characteristics. The results indicate age-related variation in FOXO1 gene expression, with higher levels observed in patients aged 68 and above. In addition, tumors originating from the rectum exhibit higher FOXO1 expression compared to colon tumors, suggesting region-specific differences in expression. The results also identify the potential correlation between PTEN, PIK3CA gene expression, and parameters such as tumor grade and neuroinvasion. The bioinformatic comparative analysis found that PTEN and FOXO1 expressions were downregulated in colorectal cancer tissue compared to normal colon tissue. Relapse-free survival analysis based on gene expression identified significant correlations, highlighting PTEN and FRAP as potential indicators of favorable outcomes. Our findings provide a deeper understanding of the role of the PI3K/AKT pathway in colorectal cancer and the importance of understanding the molecular basis of colorectal cancer development and progression.


Subject(s)
Colorectal Neoplasms , Gene Expression Regulation, Neoplastic , PTEN Phosphohydrolase , Proto-Oncogene Proteins c-akt , Signal Transduction , Humans , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/genetics , Signal Transduction/genetics , Aged , Male , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Female , Middle Aged , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol 3-Kinases/genetics , Class I Phosphatidylinositol 3-Kinases/genetics , Class I Phosphatidylinositol 3-Kinases/metabolism , Forkhead Box Protein O1/genetics , Forkhead Box Protein O1/metabolism , Adult , Aged, 80 and over
3.
Int J Mol Sci ; 25(11)2024 May 28.
Article in English | MEDLINE | ID: mdl-38892054

ABSTRACT

MicroRNAs (miRNAs) are small RNA molecules that regulate more than 30% of genes in humans. Recent studies have revealed that miRNAs play a crucial role in tumorigenesis. Large sets of miRNAs in human tumors are under-expressed compared to normal tissues. Furthermore, experiments have shown that interference with miRNA processing enhances tumorigenesis. Multiple studies have documented the causal role of miRNAs in cancer, and miRNA-based anticancer therapies are currently being developed. This review primarily focuses on two key points: (1) miRNAs and their role in human cancer and (2) the regulation of tumor suppressors by miRNAs. The review discusses (a) the regulation of the tumor suppressor p53 by miRNA, (b) the critical role of the miR-144/451 cluster in regulating the Itch-p63-Ago2 pathway, and (c) the regulation of PTEN by miRNAs. Future research and the perspectives of miRNA in cancer are also discussed. Understanding these pathways will open avenues for therapeutic interventions targeting miRNA regulation.


Subject(s)
Gene Expression Regulation, Neoplastic , MicroRNAs , Neoplasms , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Neoplasms/genetics , Neoplasms/therapy , Neoplasms/metabolism , Animals , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
4.
Int J Mol Sci ; 25(11)2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38892296

ABSTRACT

As we move into the era of precision medicine, the growing relevance of genetic alterations to prostate cancer (PCa) development and treatment demonstrates the importance of characterizing preclinical models at the genomic level. Our study investigated the genomic characterization of eight PCa cell lines to understand which models are clinically relevant. We designed a custom AmpliSeq DNA gene panel that encompassed key molecular pathways targeting AR signaling, apoptosis, DNA damage repair, and PI3K/AKT/PTEN, in addition to tumor suppressor genes. We examined the relationship between cell line genomic alterations and therapeutic response. In addition, using DepMap's Celligner tool, we identified which preclinical models are most representative of specific prostate cancer patient populations on cBioPortal. These data will help investigators understand the genetic differences in preclinical models of PCa and determine which ones are relevant for use in their translational research.


Subject(s)
Genomics , Prostatic Neoplasms , Humans , Male , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Prostatic Neoplasms/metabolism , Cell Line, Tumor , Genomics/methods , Signal Transduction , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol 3-Kinases/genetics , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/genetics , DNA Repair
5.
Invest Ophthalmol Vis Sci ; 65(6): 29, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38888282

ABSTRACT

Purpose: Ubiquitination serves as a fundamental post-translational modification in numerous cellular events. Yet, its role in regulating corneal epithelial wound healing (CEWH) remains elusive. This study endeavored to determine the function and mechanism of ubiquitination in CEWH. Methods: Western blot and immunoprecipitation were used to discern ubiquitination alterations during CEWH in mice. Interventions, including neuronally expressed developmentally downregulated 4 (Nedd4) siRNA and proteasome/lysosome inhibitor, assessed their impact on CEWH. In vitro analyses, such as the scratch wound assay, MTS assay, and EdU staining, were conducted to gauge cell migration and proliferation in human corneal epithelial cells (HCECs). Moreover, transfection of miR-30/200 coupled with a luciferase activity assay ascertained their regulatory mechanism on Nedd4. Results: Global ubiquitination levels were markedly increased during the mouse CEWH. Importantly, the application of either proteasomal or lysosomal inhibitors notably impeded the healing process both in vivo and in vitro. Furthermore, Nedd4 was identified as an essential E3 ligase for CEWH. Nedd4 expression was significantly upregulated during CEWH. In vivo studies revealed that downregulation of Nedd4 substantially delayed CEWH, whereas further investigations underscored its role in regulating cell proliferation and migration, through the Stat3 pathway by targeting phosphatase and tensin homolog (PTEN). Notably, our findings pinpointed miR-30/200 family members as direct regulators of Nedd4. Conclusions: Ubiquitination holds pivotal significance in orchestrating CEWH. The critical E3 ligase Nedd4, under the regulatory purview of miR-30 and miR-200, facilitates CEWH through PTEN-mediated Stat3 signaling. This revelation sheds light on a prospective therapeutic target within the realm of CEWH.


Subject(s)
Cell Movement , Cell Proliferation , Epithelium, Corneal , Nedd4 Ubiquitin Protein Ligases , PTEN Phosphohydrolase , Ubiquitin-Protein Ligases , Ubiquitination , Wound Healing , Nedd4 Ubiquitin Protein Ligases/metabolism , Nedd4 Ubiquitin Protein Ligases/genetics , Animals , Mice , Cell Movement/physiology , Cell Proliferation/physiology , Wound Healing/physiology , PTEN Phosphohydrolase/metabolism , PTEN Phosphohydrolase/genetics , Epithelium, Corneal/metabolism , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , Humans , Mice, Inbred C57BL , Endosomal Sorting Complexes Required for Transport/metabolism , Blotting, Western , STAT3 Transcription Factor/metabolism , Cells, Cultured , Disease Models, Animal , MicroRNAs/genetics , Immunoprecipitation , Male , Gene Expression Regulation/physiology
6.
Zhonghua Bing Li Xue Za Zhi ; 53(6): 585-591, 2024 Jun 08.
Article in Chinese | MEDLINE | ID: mdl-38825904

ABSTRACT

Objective: To investigate the clinical, radiological, and pathological features of anaplastic gangliogliomas (AGGs) and to determine whether these tumors represent a distinct entity. Methods: Consecutive 667 cases of ganglioglioma (GG) diagnosed at the Xuanwu Hospital, Capital Medical University, Beijing, China between January 2015 and July 2023 were screened. Among these cases, 9 pathologically confirmed AGG cases were identified. Their clinical, radiological, treatment, and outcome data were analyzed retrospectively. Most of the tumor samples were subject to next-generation sequencing, while a subset of them were subject to DNA methylation profiling. Results: Among the 9 patients, there were five males and four females, with a median age of 8 years. Epileptic seizures (5/9) were the most frequently presented symptom. Radiological examinations showed three types of radiological manifestations: four cases showed abnormal MRI signals with no significant mass effects and mild enhancement; two cases demonstrated a mixed solid-cystic density lesion with peritumoral edema, which showed significant heterogeneous enhancement and obvious mass effects, and one case displayed cystic cavity formation with nodules on MRI, which showed evident enhancements. All cases exhibited mutations that were predicted to activate the MAP kinase signaling pathway, including seven with BRAF p.V600E mutation and two with NF1 mutation. Five AGGs with mutations involving the MAP kinase signaling pathway also had concurrent mutations, including three with CDKN2A homozygous deletion, one with a TERT promoter mutation, one with a H3F3A mutation, and one with a PTEN mutation. Conclusions: AGG exhibits a distinct spectrum of pathology, genetic mutations and clinical behaviors, differing from GG. Given these characteristics suggest that AGG may be a distinct tumor type, further expansion of the case series is needed. Therefore, a comprehensive integration of clinical, histological, and molecular analyses is required to correctly diagnose AGG. It will also help guide treatments and prognostication.


Subject(s)
Brain Neoplasms , DNA Methylation , Ganglioglioma , Magnetic Resonance Imaging , Mutation , PTEN Phosphohydrolase , Proto-Oncogene Proteins B-raf , Humans , Ganglioglioma/pathology , Ganglioglioma/genetics , Male , Female , Child , Retrospective Studies , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Brain Neoplasms/diagnostic imaging , Proto-Oncogene Proteins B-raf/genetics , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Telomerase/genetics , Histones/genetics , Histones/metabolism , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Epilepsy/pathology , Epilepsy/genetics
7.
Front Biosci (Landmark Ed) ; 29(5): 179, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38812313

ABSTRACT

Nasopharyngeal carcinoma (NPC) is an aggressive head and neck tumor that is influenced by a variety of molecular factors during its pathogenesis. Among these, the phosphatase and tensin homolog (PTEN) plays a crucial role in regulatory networks. This article systematically reviews the multifaceted functions of PTEN in NPC, including its roles in inhibiting cell proliferation, regulating migration and invasion, promoting autophagy and apoptosis, and influencing resistance to radiotherapy. Molecular factors such as long non-coding RNA, microRNA (miRNA), and circular RNA can modulate PTEN through various pathways, thereby impacting the biological behavior of NPC. In addition, PTEN is involved in regulating the tumor microenvironment of NPC, and its interaction with the Epstein-Barr virus has also recently become a focus of research. A comprehensive understanding of the PTEN regulatory network provides a foundation for future personalized and targeted therapeutic strategies. This study expands our understanding of the pathogenesis of NPC and suggests new directions in the field of tumor biology and NPC treatment.


Subject(s)
MicroRNAs , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , PTEN Phosphohydrolase , Tumor Microenvironment , Humans , PTEN Phosphohydrolase/metabolism , PTEN Phosphohydrolase/genetics , Nasopharyngeal Carcinoma/genetics , Nasopharyngeal Carcinoma/metabolism , Nasopharyngeal Carcinoma/pathology , Nasopharyngeal Neoplasms/genetics , Nasopharyngeal Neoplasms/metabolism , Nasopharyngeal Neoplasms/pathology , MicroRNAs/genetics , MicroRNAs/metabolism , Tumor Microenvironment/genetics , Cell Proliferation/genetics , Apoptosis/genetics , Gene Expression Regulation, Neoplastic , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Autophagy/genetics , Cell Movement/genetics , RNA, Circular/genetics , RNA, Circular/metabolism , RNA, Circular/physiology , Herpesvirus 4, Human/genetics , Signal Transduction
8.
Mol Cancer ; 23(1): 114, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38811984

ABSTRACT

BACKGROUND: Prostate cancer develops through malignant transformation of the prostate epithelium in a stepwise, mutation-driven process. Although activator protein-1 transcription factors such as JUN have been implicated as potential oncogenic drivers, the molecular programs contributing to prostate cancer progression are not fully understood. METHODS: We analyzed JUN expression in clinical prostate cancer samples across different stages and investigated its functional role in a Pten-deficient mouse model. We performed histopathological examinations, transcriptomic analyses and explored the senescence-associated secretory phenotype in the tumor microenvironment. RESULTS: Elevated JUN levels characterized early-stage prostate cancer and predicted improved survival in human and murine samples. Immune-phenotyping of Pten-deficient prostates revealed high accumulation of tumor-infiltrating leukocytes, particularly innate immune cells, neutrophils and macrophages as well as high levels of STAT3 activation and IL-1ß production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1ß and accelerated prostate tumor growth. Comparative transcriptome profiling of prostate epithelial cells revealed a senescence-associated gene signature, upregulation of pro-inflammatory processes involved in immune cell attraction and of chemokines such as IL-1ß, TNF-α, CCL3 and CCL8 in Pten-deficient prostates. Strikingly, JUN depletion reversed both the senescence-associated secretory phenotype and senescence-associated immune cell infiltration but had no impact on cell cycle arrest. As a result, JUN depletion in Pten-deficient prostates interfered with the senescence-associated immune clearance and accelerated tumor growth. CONCLUSIONS: Our results suggest that JUN acts as tumor-suppressor and decelerates the progression of prostate cancer by transcriptional regulation of senescence- and inflammation-associated genes. This study opens avenues for novel treatment strategies that could impede disease progression and improve patient outcomes.


Subject(s)
Disease Progression , PTEN Phosphohydrolase , Prostatic Neoplasms , Tumor Microenvironment , Male , Prostatic Neoplasms/pathology , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Animals , Mice , Humans , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Tumor Microenvironment/immunology , Senescence-Associated Secretory Phenotype , Proto-Oncogene Proteins c-jun/metabolism , Gene Expression Regulation, Neoplastic , Cell Line, Tumor , Gene Expression Profiling , Cellular Senescence/genetics , Disease Models, Animal
9.
Sci Rep ; 14(1): 12280, 2024 05 29.
Article in English | MEDLINE | ID: mdl-38811827

ABSTRACT

Loss of the tumor suppressor PTEN homolog daf-18 in Caenorhabditis elegans (C. elegans) triggers diapause cell division during L1 arrest. While prior studies have delved into established pathways, our investigation takes an innovative route. Through forward genetic screening in C. elegans, we pinpoint a new player, F12E12.11, regulated by daf-18, impacting cell proliferation independently of PTEN's typical phosphatase activity. F12E12.11 is an ortholog of human estradiol 17-beta-dehydrogenase 8 (HSD17B8), which converts estradiol to estrone through its NAD-dependent 17-beta-hydroxysteroid dehydrogenase activity. We found that PTEN engages in a physical interplay with HSD17B8, introducing a distinctive suppression mechanism. The reduction in estrone levels and accumulation of estradiol may arrest tumor cells in the G2/M phase of the cell cycle through MAPK/ERK. Our study illuminates an unconventional protein interplay, providing insights into how PTEN modulates tumor suppression by restraining cell division through intricate molecular interactions.


Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans , Cell Proliferation , PTEN Phosphohydrolase , PTEN Phosphohydrolase/metabolism , PTEN Phosphohydrolase/genetics , Animals , Caenorhabditis elegans/metabolism , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans Proteins/genetics , Humans , 17-Hydroxysteroid Dehydrogenases/metabolism , 17-Hydroxysteroid Dehydrogenases/genetics , Estradiol/metabolism , Estrone/metabolism
10.
Int J Chron Obstruct Pulmon Dis ; 19: 1141-1151, 2024.
Article in English | MEDLINE | ID: mdl-38817823

ABSTRACT

Background: This study sought to explore the underlying mechanism of miR-21 mediated apoptosis and inflammation in chronic obstructive pulmonary disease (COPD) induced by cigarette smoke (CS). Methods: We detected levels and PTEN/Akt/NF-κB axis protein levels in peripheral lung tissues of COPD patients and CS-exposed mice and HBE cells. Western blotting assay was used to determine the expression of cleaved caspase-3. IL-6 and IL-8 protein was detected in cell supernatant from cells by ELISA. HBE cells were transfected with a miR-21 inhibitor, and co-culture with A549. Results: Increased miR-21 expression, reduced PTEN expression and following activation of Akt in in peripheral lung tissues of COPD patients and CS-exposed mice and HBE cells. Inhibition of miR-21 showed enhanced PTEN levels and reduced the expression of phosphorylated form of Akt and NF-κB. Decreased expression of cleaved caspase-3, IL-6 and IL-8 in A549 cells co cultured with HBE cells transfected with miR-21 inhibitor compared with transfected with miR-21 control inhibitor. Conclusion: MiR-21 contributes to COPD pathogenesis by modulating apoptosis and inflammation through the PTEN/Akt/NF-κB pathway. Targeting miR-21 may increase PTEN expression and inhibit Akt/NF-κB pathway, offering potential diagnostic and therapeutic value in COPD management.


Subject(s)
Apoptosis , Disease Models, Animal , Lung , MicroRNAs , NF-kappa B , PTEN Phosphohydrolase , Proto-Oncogene Proteins c-akt , Pulmonary Disease, Chronic Obstructive , Signal Transduction , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/genetics , Pulmonary Disease, Chronic Obstructive/pathology , MicroRNAs/metabolism , MicroRNAs/genetics , PTEN Phosphohydrolase/metabolism , PTEN Phosphohydrolase/genetics , Humans , Proto-Oncogene Proteins c-akt/metabolism , Animals , NF-kappa B/metabolism , A549 Cells , Lung/pathology , Lung/metabolism , Male , Middle Aged , Female , Mice, Inbred C57BL , Interleukin-8/metabolism , Inflammation Mediators/metabolism , Interleukin-6/metabolism , Phosphorylation , Cigarette Smoking/adverse effects , Case-Control Studies , Aged
11.
Redox Biol ; 73: 103200, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38781729

ABSTRACT

Currently, chemotherapy remains occupying a pivotal place in the treatment of pancreatic ductal adenocarcinoma (PDAC). Nonetheless, the emergence of drug resistance in recent years has limited the clinical efficacy of chemotherapeutic agents, especially gemcitabine (GEM). Through bioinformatics analysis, AT-rich Interactive Domain-containing Protein 3A (ARID3A), one of transcription factors, is discovered to possibly participate in this progress. This study thoroughly investigates the potential role of ARID3A in the malignant progression and GEM chemoresistance of PDAC and explores the underlying mechanisms. The results indicate that ARID3A knockdown suppresses tumor development and enhances the sensitivity of PDAC cells to GEM in vitro and vivo. Mechanically, CUT&Tag profiling sequencing, RNA-sequencing and functional studies demonstrates that decreased ARID3A expression alleviates the transcriptional inhibition of phosphatase and tensin homolog (PTEN), consequently leading to glutathione peroxidase 4 (GPX4) depletion and increased lipid peroxidation levels. Activated ferroptosis induced by the inhibition of GPX4 subsequently restricts tumor progression and reduces GEM resistance in PDAC. This research identifies the ferroptosis regulatory pathway of ARID3A-PTEN-GPX4 axis and reveals its critical role in driving the progression and chemoresistance of pancreatic cancer. Notably, both inhibition of ARID3A and enhancement of ferroptosis can increase chemosensitivity to GEM, which offers a promising opportunity for developing therapeutic strategies to combat acquired chemotherapy resistance in pancreatic cancer.


Subject(s)
DNA-Binding Proteins , Drug Resistance, Neoplasm , Ferroptosis , Gene Expression Regulation, Neoplastic , PTEN Phosphohydrolase , Pancreatic Neoplasms , Transcription Factors , Ferroptosis/drug effects , Ferroptosis/genetics , Humans , PTEN Phosphohydrolase/metabolism , PTEN Phosphohydrolase/genetics , Drug Resistance, Neoplasm/genetics , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Mice , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , Animals , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Gemcitabine , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Cell Proliferation/drug effects , Xenograft Model Antitumor Assays , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics
12.
Cell Commun Signal ; 22(1): 252, 2024 May 02.
Article in English | MEDLINE | ID: mdl-38698453

ABSTRACT

BACKGROUND: Ischemic postconditioning (IPostC) has been reported as a promising method for protecting against myocardial ischemia-reperfusion (MI/R) injury. Our previous study found that the infarct-limiting effect of IPostC is abolished in the heart of diabetes whose cardiac expression of DJ-1 (also called PARK7, Parkinsonism associated deglycase) is reduced. However, the role and in particular the underlying mechanism of DJ-1 in the loss of sensitivity to IPostC-induced cardioprotection in diabetic hearts remains unclear. METHODS: Streptozotocin-induced type 1 diabetic rats were subjected to MI/R injury by occluding the left anterior descending artery (LAD) and followed by reperfusion. IPostC was induced by three cycles of 10s of reperfusion and ischemia at the onset of reperfusion. AAV9-CMV-DJ-1, AAV9-CMV-C106S-DJ-1 or AAV9-DJ-1 siRNA were injected via tail vein to either over-express or knock-down DJ-1 three weeks before inducing MI/R. RESULTS: Diabetic rats subjected to MI/R exhibited larger infarct area, more severe oxidative injury concomitant with significantly reduced cardiac DJ-1 expression and increased PTEN expression as compared to non-diabetic rats. AAV9-mediated cardiac DJ-1 overexpression, but not the cardiac overexpression of DJ-1 mutant C106S, restored IPostC-induced cardioprotection and this effect was accompanied by increased cytoplasmic DJ-1 translocation toward nuclear and mitochondrial, reduced PTEN expression, and increased Nrf-2/HO-1 transcription. Our further study showed that AAV9-mediated targeted DJ-1 gene knockdown aggravated MI/R injury in diabetic hearts, and this exacerbation of MI/R injury was partially reversed by IPostC in the presence of PTEN inhibition or Nrf-2 activation. CONCLUSIONS: These findings suggest that DJ-1 preserves the cardioprotective effect of IPostC against MI/R injury in diabetic rats through nuclear and mitochondrial DJ-1 translocation and that inhibition of cardiac PTEN and activation of Nrf-2/HO-1 may represent the major downstream mechanisms whereby DJ-1 preserves the cardioprotective effect of IPostC in diabetes.


Subject(s)
Diabetes Mellitus, Experimental , Ischemic Postconditioning , Myocardial Reperfusion Injury , PTEN Phosphohydrolase , Protein Deglycase DJ-1 , Rats, Sprague-Dawley , Animals , Protein Deglycase DJ-1/metabolism , Protein Deglycase DJ-1/genetics , PTEN Phosphohydrolase/metabolism , PTEN Phosphohydrolase/genetics , Diabetes Mellitus, Experimental/metabolism , Male , Rats , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/pathology , Myocardial Reperfusion Injury/genetics , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/genetics , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 1/complications , Protein Transport , Streptozocin , Myocardial Infarction/metabolism , Myocardial Infarction/pathology
13.
Biochem Biophys Res Commun ; 718: 149981, 2024 Jul 23.
Article in English | MEDLINE | ID: mdl-38735134

ABSTRACT

In animal cells, vacuoles are absent, but can be induced by diseases and drugs. While phosphoinositides are critical for membrane trafficking, their role in the formation of these vacuoles remains unclear. The immunosuppressive KRP203/Mocravimod, which antagonizes sphingosine-1-phosphate receptors, has been identified as having novel multimodal activity against phosphoinositide kinases. However, the impact of this novel KRP203 activity is unknown. Here, we show that KRP203 disrupts the spatial organization of phosphoinositides and induces extensive vacuolization in tumor cells and immortalized fibroblasts. The KRP203-induced vacuoles are primarily from endosomes, and augmented by inhibition of PIKFYVE and VPS34. Conversely, overexpression of PTEN decreased KRP203-induced vacuole formation. Furthermore, V-ATPase inhibition completely blunted KRP203-induced vacuolization, pointing to a critical requirement of the endosomal maturation process. Importantly, nearly a half of KRP203-induced vacuoles are significantly decorated with PI4P, a phosphoinositide typically enriched at the plasma membrane and Golgi. These results suggest a model that noncanonical spatial reorganization of phosphoinositides by KRP203 alters the endosomal maturation process, leading to vacuolization. Taken together, this study reveals a previously unrecognized bioactivity of KRP203 as a vacuole-inducing agent and its unique mechanism of phosphoinositide modulation, providing a new insight of phosphoinositide regulation into vacuolization-associated diseases and their molecular pathologies.


Subject(s)
Endosomes , PTEN Phosphohydrolase , Phosphatidylinositols , Vacuoles , Vacuoles/metabolism , Vacuoles/drug effects , Endosomes/metabolism , Endosomes/drug effects , Humans , Phosphatidylinositols/metabolism , Animals , PTEN Phosphohydrolase/metabolism , PTEN Phosphohydrolase/genetics , Phosphatidylinositol 3-Kinases/metabolism , Class III Phosphatidylinositol 3-Kinases/metabolism , Class III Phosphatidylinositol 3-Kinases/genetics , Mice , Morpholines/pharmacology , Vacuolar Proton-Translocating ATPases/metabolism , Vacuolar Proton-Translocating ATPases/antagonists & inhibitors , Vacuolar Proton-Translocating ATPases/genetics , Cytoplasm/metabolism , HeLa Cells , Aminopyridines , Heterocyclic Compounds, 3-Ring
14.
Transl Res ; 271: 79-92, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38797432

ABSTRACT

Hepatocellular carcinoma (HCC) is among the most fatal types of malignancy, with a high prevalence of relapse and limited treatment options. As a critical regulator of ferroptosis and redox homeostasis, glutathione peroxidase 4 (GPX4) is commonly upregulated in HCC and is hypothesized to facilitate cancer metastasis, but this has not been fully explored in HCC. Here, we report that up-regulated GPX4 expression in HCC is strongly associated with tumor metastasis. FACS-based in vivo and in vitro analysis revealed that a cell subpopulation featuring lower cellular reactive oxygen species levels and ferroptosis resistance were involved in GPX4-mediated HCC metastasis. Mechanistically, GPX4 overexpressed in HCC tumor cells was enriched in the nucleus and transcriptionally silenced GRHL3 expression, thereby activating PTEN/PI3K/AKT signaling and promoting HCC metastasis. Functional studies demonstrated that GPX4 amino acids 110-145 are a binding site that interacts with the GRHL3 promoter. As AKT is a downstream target of GPX4, we combined the AKT inhibitor, AKT-IN3, with lenvatinib to effectively inhibit HCC tumor cell metastasis. Overall, these results indicate that the GPX4/GRHL3/PTEN/PI3K/AKT axis controls HCC cell metastasis and lenvatinib combined with AKT-IN3 represents a potential therapeutic strategy for patients with metastatic HCC.


Subject(s)
Carcinoma, Hepatocellular , DNA-Binding Proteins , Liver Neoplasms , Neoplasm Metastasis , PTEN Phosphohydrolase , Phosphatidylinositol 3-Kinases , Phospholipid Hydroperoxide Glutathione Peroxidase , Proto-Oncogene Proteins c-akt , Signal Transduction , Transcription Factors , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/genetics , Liver Neoplasms/pathology , PTEN Phosphohydrolase/metabolism , PTEN Phosphohydrolase/genetics , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Animals , Transcription Factors/metabolism , Transcription Factors/genetics , Cell Line, Tumor , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/metabolism , Mice , Gene Expression Regulation, Neoplastic , Male , Mice, Nude , Transcription, Genetic
15.
Cell Rep ; 43(5): 114173, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38700984

ABSTRACT

Mutations in the phosphatase and tensin homolog (PTEN) gene are associated with severe neurodevelopmental disorders. Loss of PTEN leads to hyperactivation of the mechanistic target of rapamycin (mTOR), which functions in two distinct protein complexes, mTORC1 and mTORC2. The downstream signaling mechanisms that contribute to PTEN mutant phenotypes are not well delineated. Here, we show that pluripotent stem cell-derived PTEN mutant human neurons, neural precursors, and cortical organoids recapitulate disease-relevant phenotypes, including hypertrophy, electrical hyperactivity, enhanced proliferation, and structural overgrowth. PTEN loss leads to simultaneous hyperactivation of mTORC1 and mTORC2. We dissect the contribution of mTORC1 and mTORC2 by generating double mutants of PTEN and RPTOR or RICTOR, respectively. Our results reveal that the synergistic hyperactivation of both mTORC1 and mTORC2 is essential for the PTEN mutant human neural phenotypes. Together, our findings provide insights into the molecular mechanisms that underlie PTEN-related neural disorders and highlight novel therapeutic targets.


Subject(s)
Mechanistic Target of Rapamycin Complex 1 , Mechanistic Target of Rapamycin Complex 2 , Neurons , Organoids , PTEN Phosphohydrolase , Humans , PTEN Phosphohydrolase/metabolism , PTEN Phosphohydrolase/genetics , Mechanistic Target of Rapamycin Complex 1/metabolism , Organoids/metabolism , Neurons/metabolism , Mechanistic Target of Rapamycin Complex 2/metabolism , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Mutation/genetics , Rapamycin-Insensitive Companion of mTOR Protein/metabolism , Rapamycin-Insensitive Companion of mTOR Protein/genetics , Signal Transduction , Cell Proliferation , Regulatory-Associated Protein of mTOR/metabolism , Regulatory-Associated Protein of mTOR/genetics , Phenotype
16.
Anticancer Res ; 44(6): 2567-2575, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38821612

ABSTRACT

BACKGROUND/AIM: Protein phosphatase and tensin homolog (PTEN) is a tumor suppressor protein with potential to be a new biotechnological drug for PTEN-deficient cancer treatment. This study aimed to develop PTEN-based chimeric proteins (CPP-PTEN-THP) for human epidermal growth factor receptor 2 (HER2)-positive breast cancer treatment, addressing current limitations like inadequate delivery, poor tumor penetration, and low selectivity, while assessing their potential HER2-specific anticancer effects. MATERIALS AND METHODS: pCEFL-EGFP vector was used for both TAT-PTEN-LTV and KLA-PTEN-LTV construction. Non-contact co-cultures were employed using HEK-293T cells for protein expression, and HCC-1954 and MCF-7 cell lines for cytotoxicity testing. Protein detection was analyzed by western blotting and a docking prediction analysis was performed to infer the interactions. RESULTS: Endogenous and recombinant PTEN protein expression was confirmed in cell lysates. A 54-kDa signal matching the theoretical size of PTEN was detected, showing a greater level in TAT-PTEN-LTV (215.1±26.45%) and KLA-PTEN-LTV (129.2±1.44%) compared to endogenous PTEN. After the noncontact co-culture method, cytotoxic studies showed HCC-1954 preferential cell inhibition growth, with 25.95±0.9% and 12.25±1.29% inhibition by KLA-PTEN-LTV and TAT-PTEN-LTV respectively, compared to MCF-7 cells. An LTV-HER2 interaction model was proposed, inferring that LTV interactions are mainly due to the Pro, Trp, and Tyr residues that target HER2. CONCLUSION: The developed PTEN-based chimeric proteins have HER2-specific anticancer activity against HCC-1954 cells.


Subject(s)
PTEN Phosphohydrolase , Receptor, ErbB-2 , Recombinant Fusion Proteins , Humans , PTEN Phosphohydrolase/metabolism , PTEN Phosphohydrolase/genetics , Receptor, ErbB-2/metabolism , Receptor, ErbB-2/genetics , Recombinant Fusion Proteins/pharmacology , Recombinant Fusion Proteins/metabolism , Recombinant Fusion Proteins/genetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , HEK293 Cells , MCF-7 Cells , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Breast Neoplasms/genetics , Female , Molecular Docking Simulation , Coculture Techniques
17.
Biomed Pharmacother ; 175: 116739, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38759288

ABSTRACT

BACKGROUND: Ketamine, as a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, was originally used in general anesthesia. Epidemiological data show that ketamine has become one of the most commonly abused drugs in China. Ketamine administration might cause cognitive impairment; however, its molecular mechanism remains unclear. The glymphatic system is a lymphoid system that plays a key role in metabolic waste removal and cognitive regulation in the central nervous system. METHODS: Focusing on the glymphatic system, this study evaluated the behavioral performance and circulatory function of the glymphatic system by building a short-term ketamine administration model in mice, and detected the expression levels of the 5-HT2c receptor, ΔFosb, Pten, Akt, and Aqp4 in the hippocampus. Primary astrocytes were cultured to verify the regulatory relationships among related indexes using a 5-HT2c receptor antagonist, a 5-HT2c receptor short interfering RNA (siRNA), and a ΔFosb siRNA. RESULTS: Ketamine administration induced ΔFosb accumulation by increasing 5-HT2c receptor expression in mouse hippocampal astrocytes and primary astrocytes. ΔFosb acted as a transcription factor to recognize the AATGATTAAT bases in the 5' regulatory region of the Aqp4 gene (-1096 bp to -1087 bp), which inhibited Aqp4 expression, thus causing the circulatory dysfunction of the glymphatic system, leading to cognitive impairment. CONCLUSIONS: Although this regulatory mechanism does not involve the Pten/Akt pathway, this study revealed a new mechanism of ketamine-induced cognitive impairment in non-neuronal systems, and provided a theoretical basis for the safety of clinical treatment and the effectiveness of withdrawal.


Subject(s)
Astrocytes , Cognitive Dysfunction , Glymphatic System , Hippocampus , Ketamine , Animals , Ketamine/pharmacology , Ketamine/toxicity , Astrocytes/drug effects , Astrocytes/metabolism , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/metabolism , Mice , Male , Hippocampus/drug effects , Hippocampus/metabolism , Glymphatic System/drug effects , Glymphatic System/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Aquaporin 4/metabolism , Aquaporin 4/genetics , Receptor, Serotonin, 5-HT2C/metabolism , Receptor, Serotonin, 5-HT2C/genetics , Mice, Inbred C57BL , Cells, Cultured , Proto-Oncogene Proteins c-fos/metabolism , Proto-Oncogene Proteins c-fos/genetics , PTEN Phosphohydrolase/metabolism , PTEN Phosphohydrolase/genetics
18.
J Pathol ; 263(3): 275-287, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38734880

ABSTRACT

The hyperplasia-carcinoma sequence is a stepwise tumourigenic programme towards endometrial cancer in which normal endometrial epithelium becomes neoplastic through non-atypical endometrial hyperplasia (NAEH) and atypical endometrial hyperplasia (AEH), under the influence of unopposed oestrogen. NAEH and AEH are known to exhibit polyclonal and monoclonal cell growth, respectively; yet, aside from focal PTEN protein loss, the genetic and epigenetic alterations that occur during the cellular transition remain largely unknown. We sought to explore the potential molecular mechanisms that promote the NAEH-AEH transition and identify molecular markers that could help to differentiate between these two states. We conducted target-panel sequencing on the coding exons of 596 genes, including 96 endometrial cancer driver genes, and DNA methylome microarrays for 48 NAEH and 44 AEH lesions that were separately collected via macro- or micro-dissection from the endometrial tissues of 30 cases. Sequencing analyses revealed acquisition of the PTEN mutation and the clonal expansion of tumour cells in AEH samples. Further, across the transition, alterations to the DNA methylome were characterised by hypermethylation of promoter/enhancer regions and CpG islands, as well as hypo- and hyper-methylation of DNA-binding regions for transcription factors relevant to endometrial cell differentiation and/or tumourigenesis, including FOXA2, SOX17, and HAND2. The identified DNA methylation signature distinguishing NAEH and AEH lesions was reproducible in a validation cohort with modest discriminative capability. These findings not only support the concept that the transition from NAEH to AEH is an essential step within neoplastic cell transformation of endometrial epithelium but also provide deep insight into the molecular mechanism of the tumourigenic programme. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Subject(s)
Carcinoma, Endometrioid , DNA Methylation , Endometrial Hyperplasia , Endometrial Neoplasms , Epigenesis, Genetic , PTEN Phosphohydrolase , Female , Humans , Endometrial Neoplasms/genetics , Endometrial Neoplasms/pathology , Carcinoma, Endometrioid/genetics , Carcinoma, Endometrioid/pathology , PTEN Phosphohydrolase/genetics , Endometrial Hyperplasia/genetics , Endometrial Hyperplasia/pathology , Endometrial Hyperplasia/metabolism , Precancerous Conditions/genetics , Precancerous Conditions/pathology , Mutation , Gene Expression Regulation, Neoplastic , Middle Aged , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , CpG Islands/genetics , Aged
19.
Sci Rep ; 14(1): 12020, 2024 05 26.
Article in English | MEDLINE | ID: mdl-38797813

ABSTRACT

In the face of recent advances in Cervical cancer (CC) treatment, therapeutic and surgical procedures for CC management are still inadequate. In the current study for the first time Andrographolide (Andro) has been explored for its multitarget therapeutic efficacy on NF-kB, COX-2, and PI3K/AKT expressions together in CC. The expression levels of NF-kB, COX-2, PI3K and PTEN in the CC patient samples, both at mRNA and protein levels have shown significant association with poor survival and increased tumor aggressiveness. The binding efficacy of Andro was investigated using molecular docking and molecular dynamic simulations, and the protein and ligand complex for NF-kB and COX-2 has shown high binding energy. Andro displayed cytotoxicity by impeding the in-vitro proliferation of CC cells. Andro significantly supressed the NF-kB, COX-2, and PI3K expression and enhanced the expression levels of PTEN at protein levels in-vitro. Andro induced apoptosis in a dose dependent manner and significantly inhibited the migration and invasion of CC cells. Andro exhibited similar activity in-vivo and suppressed the CC tumor growth in xenograft C57BL/6 mice model. The anti-tumor activity of Andro, both in-vitro and in-vivo has shown considerable downregulation of NF-kB and COX-2 and induced apoptosis through impeding the PI3K/AKT signalling pathway. These findings from the above study projects, administration of Andro as an effective alternate safe compound to curtail and impede cervical cancer progression.


Subject(s)
Cyclooxygenase 2 , Diterpenes , NF-kappa B , PTEN Phosphohydrolase , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Signal Transduction , Uterine Cervical Neoplasms , Uterine Cervical Neoplasms/drug therapy , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/genetics , Humans , PTEN Phosphohydrolase/metabolism , PTEN Phosphohydrolase/genetics , Female , Diterpenes/pharmacology , NF-kappa B/metabolism , Signal Transduction/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Animals , Phosphatidylinositol 3-Kinases/metabolism , Mice , Cyclooxygenase 2/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Apoptosis/drug effects , Molecular Docking Simulation , Xenograft Model Antitumor Assays , Disease Progression , Gene Expression Regulation, Neoplastic/drug effects , Cell Movement/drug effects
20.
Cell Death Dis ; 15(5): 335, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38744853

ABSTRACT

PTENα/ß, two variants of PTEN, play a key role in promoting tumor growth by interacting with WDR5 through their N-terminal extensions (NTEs). This interaction facilitates the recruitment of the SET1/MLL methyltransferase complex, resulting in histone H3K4 trimethylation and upregulation of oncogenes such as NOTCH3, which in turn promotes tumor growth. However, the molecular mechanism underlying this interaction has remained elusive. In this study, we determined the first crystal structure of PTENα-NTE in complex with WDR5, which reveals that PTENα utilizes a unique binding motif of a sequence SSSRRSS found in the NTE domain of PTENα/ß to specifically bind to the WIN site of WDR5. Disruption of this interaction significantly impedes cell proliferation and tumor growth, highlighting the potential of the WIN site inhibitors of WDR5 as a way of therapeutic intervention of the PTENα/ß associated cancers. These findings not only shed light on the important role of the PTENα/ß-WDR5 interaction in carcinogenesis, but also present a promising avenue for developing cancer treatments that target this pathway.


Subject(s)
Intracellular Signaling Peptides and Proteins , PTEN Phosphohydrolase , PTEN Phosphohydrolase/metabolism , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/chemistry , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/chemistry , Animals , Mice , Neoplasms/genetics , Neoplasms/pathology , Neoplasms/metabolism , Cell Proliferation/genetics , Disease Progression , Protein Binding , Cell Line, Tumor , Mice, Nude , Histone-Lysine N-Methyltransferase/metabolism , Histone-Lysine N-Methyltransferase/genetics , Histone-Lysine N-Methyltransferase/chemistry , Protein Domains , Amino Acid Motifs
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