Proteomics of Prostate Cancer Tissue Small Extracellular Vesicles Reveal Alteration of Metabolism
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
SUBMITTER: 
Lijuan Yu
PROVIDER: PXD070085 | iProX | Thu Oct 30 00:00:00 GMT 2025
REPOSITORIES: iProX
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Project description:Tumor-derived extracellular vesicles (EVs) play an important role in cancer pro-gression. Neutral Sphingomyelinases (nSMases) are lipid modifying enzymes that modu-late the secretion of EVs from cells. How nSMase activity and therefore ceramide genera-tion affects the composition and functionality of secreted EV is not fully understood. Here, we aimed to investigated the expression of nSMases 1 and 2 in prostate cancer (PCa) tissue and their role in EV composition and secretion for prostate cancer cell migration. Reduced nSMase 1 and 2 expression was found in prostate cancer and correlated with age of pa-tients. When nSMase 2 was inhibited by GW4869 in PCa cells, PC3 and DU145, the EV se-cretome was significantly altered, while the number of EVs and total protein content of the released EVs were not significantly changed. Using proteomics analysis, we found extra-cellular matrix proteins, such as SDC4 (Syndecan-4) and SRPX-2 differentially secreted on EVs from GW4869-treated PC3 cells. In scratch wound migration assays, GW4869 signifi-cantly increased migration compared to control PC3 cells but not DU145 cells, while SDC4 knockdown significantly reduced migration of PC3 cells. These and other nSMase 2-dependent secreted proteins are interesting candidates to understand the role of stress-induced EV in the progression of prostate cancer.
2025-05-07 | PXD062469 | Pride
Project description:Malonyl-CoA, as a key metabolite, is not only the building block for lipogenesis, but also a critical metabolic switcher to mediates flux control over mitochondrial FAs β-oxidation in cellular. However, the levels and entire functions of malonyl-CoA in malignancy and drug resistance is still unclear, especially in those characterized by abnormal lipid metabolism, such as prostate cancer (PCa). Here, we showed the levels of malonyl CoA was increased in PCa, especially in castration-resistant prostate cancer (CRPC). Abnormal accumulation of malonyl-CoA promoted lipogenesis and reprogramed multiple metabolism (including lipid, glucose and amino acid metabolism), sustaining cellular homeostasis to contribute to PCa progression. Restoration of MLYCD expression activated PREK-mediated unfolded protein reaction (UPR) via consuming malonyl-CoA. Importantly, we also found that malonyl-CoA as a donor of malonylation, promoted lysine malonylation in PCa. We identified that malonyl-CoA promoted Ran K141 malonylation, increasing Ran activity and enhancing AR nuclear translocation and transcriptional activity, finally contributing to PCa development and resistance to antiandrogens. These findings highlighted the previously unrecognized role and function of MLYCD-mediated malonyl-CoA in PCa progression via the canonical pathway (metabolic reprogramming) and the non-canonical pathway (malonylated Ran K141), systematically revealing that might be a potentially reliable biomarker and therapy for PCa.
2025-08-21 | PXD060607 | Pride
Project description:Radiotherapy represents a major curative treatment for prostate cancer (PCa), but some patients will develop radioresistance (RR) and relapse. The underlying mechanisms remain poorly understood, and miRNAs might be key players in the acquisition and maintenance of RR. Through their encapsulation in small extracellular vesicles (EVs), they can also be relevant biomarkers of radiation response. Using next-generation sequencing, we found that miR-200c-3p was downregulated in PCa RR cells and in their small EVs due to a gain of methylation on its promoter during RR acquisition. We next showed that its exogenous overexpression restores the radiosensitivity of RR cells by delaying DNA repair through the targeting of HP1α. Interestingly, we also observed downregulation of miR-200c-3p expression by DNA methylation in radiation-resistant lung and breast cancer cell lines. In summary, our study demonstrates that the downregulation of miR-200c-3p expression in PCa cells and in their small EVs could help distinguish radioresistant from sensitive tumor cells. This miRNA targets HP1α to delay DNA repair and promote cell death.
2025-01-01 | GSE268975 | GEO
Project description:Prostate cancer (PCa) remains the malignancy with the highest morbidity in men (1). Although early-stage PCa usually causes no symptoms, cancer cells in prostate glands readily metastasize to bones, lymph nodes, lungs, and liver during PCa progression (2). Common strategies, including surgery, radiation therapy, and androgen-deprivation therapy, are promising treatments for early-stage PCa. However, advanced PCa still lacks effective therapeutic strategies (3-5). Thus, researchers are currently focused on inhibiting tumor progression to explore effective therapeutic strategies for PCa treatment (6, 7). Cancer-associated fibroblasts (CAFs), stromal cells derived from normal fibroblasts or epithelia, are one of the major cellular components in the tumor microenvironment (8, 9). Compared with normal fibroblasts, CAFs are activated with increased expression of key protein markers, such as α-SMA, FAP, vimentin and S100A4 protein (10, 11). In the tumor microenvironment, CAFs secrete various growth effectors or cytokines to the extracellular matrix and thereby promote tumor progression by directly enhancing cancer cell growth, angiogenic induction, the extracellular matrix modification, and tumor-promoting inflammatory mediation (11-14). Notably, CAFs could act as an immunosuppressive mediator for the formation of an immunosuppressive tumor environment by recruiting and activating multiple immune cells (15). As such, CAFs might be a potential target in anti-tumor immunotherapy (16, 17). Currently, increased research has focused on inhibiting the immunosuppressive function of prostate cancer-associated fibroblasts (prostate CAFs), which may suggest therapeutic strategies for PCa (18, 19). Polysaccharides from Lentinus edodes are known to exhibit potent anti-tumor and immunomodulatory functions. The anti-tumor mechanisms of L. edodes polysaccharides include regulating the innate immune system by mediating CAF function, preventing tumorigenesis, or directly killing tumor cells via cell cycle regulation or apoptotic induction (20-22). Our previous studies isolated a novel polysaccharide component (MPSSS) from L. edodes. We found the secretome of prostate CAFs treated with MPSSS could inhibit the proliferation of CD4+ and CD8+ T cells, which suggested that MPSSS could prevent the immunosuppressive function of prostate CAFs (22). However, although the secretome of MPSSS-treated prostate CAFs inhibit the proliferation of T cells, how the secretome of MPSSS-treated prostate CAFs affect PCa progression is still unclear. The secretome defines as all proteins secreted by the organism or living cells into the extracellular space, which consists of soluble proteins and extracellular vesicles (EVs) (23). The secretome of prostate CAFs pays vital roles in PCa tumor origination, progression (24, 25). Since EVs contains various molecules (proteins, RNA, DNA and lipid) (26), we speculate that soluble proteins and EVs of prostate CAFs might have the different influence on PCa cells. In this study, the secretome of prostate CAFs untreated/treated with MPSSS were separated into the high molecular weight secretome (>100 kD) and the low molecular weight secretome (3-100 kD) using 100 kD and 3kD MWCO memberane filtration to narrow down the range of active components. The high molecular weight secretome contained extracellular vesicles (EVs) and large soluble proteins, while the low molecular weight secretome contained the small soluble proteins. The secretome of prostate CAFs untreated/treated with MPSSS were used to explore the underlying function and molecular mechanism using quantitative proteomics and multiple biochemical approaches.
2021-03-22 | PXD023689 | Pride
Project description:Long noncoding (lnc)RNA modulate gene expression alongside presenting unexpected source of neoantigens. Despite their immense interest, little is known in their ability to be transferred and control adjacent cells. Extracellular Vesicles (EVs) offer a protective environment for nucleic acids, with pro and anti-tumorigenic functions by controlling the immune response. However, few studies have addressed the full RNA content of EVs in human fluids and none have compared them with their tissue of origin. Here, we performed Total RNA-Sequencing on 6 Formaldehyde-Fixed-Parafilm-Embedded (FFPE) prostate cancer (PCa) tumor tissues and their paired urinary (u)EVs to provide the first whole transcriptome comparison from the same patients. uEVs contain intron-free cytoplasmic transcripts, specific lnc/circular (circ)RNAs. Some uEV-circRNA were characterized as essential for prostate cell proliferation in vitro. 15 uEV-lncRNA were predicted encoding 750 unique high-affinity neoantigens. Our comparison of functional EVs-lnc/circRNAs in 3 PCa cell lines provides a fundamental resource to determine the role of uEV-lncRNA in PCa progression.
2022-05-18 | GSE183070 | GEO
Project description:Prostate cancer (PCa) is the second most common cancer and fifth leading cause of cance death among men worldwide. Intriguingly, primary prostate tumors do not undergo a metabolic switch from oxidative phosphorylation to aerobic glycolysis to meet increased energetic and biosynthetic demand for cell growth and division. In contrast, PCa cells preferentially use fatty acids for metabolic fuel, and malignant transformation of prostate tissue is accompanied by a sustained increase in the activity of both lipogenic and oxidative enzymes. As peroxisomes (PO) play a key role in cellular lipid and redox metabolism, it may not come as a surprise that these organelles are increasingly recognized as being involved in the pathogenesis of PCa. However, many uncertainties and inadequacies in our understanding of how PO function in PCa progression remain. This project is intended to gain a more coherent picture of how alterations in PO metabolism contribute to PCa development, progression, and therapy response. Specifically, by employing cutting-edge technologies, we systematically inventory which peroxisomal parameters are affected in commonly used cell models of PCa.
2024-11-01 | PXD054270 | Pride
Project description:Laser Capture Microdissected cells from archival FFPE Prostate cancer and normal adjacent tissues from 10 patients (5 CA and 5 AA) were converted to cDNA and analysed by PCR array to identify differentially expressed miRNAs between the groups. Selected differentially expressed miRNAs were further validated in tissues from 40 prostate cancer patients. The miRNAs which were differentially modulated in PCa patients in the validation set were further analysed in 32 urine samples from PCa patients and compared with 12 healthy individuals. Differentially expressed miRNAs were explored to e used as non-invasive biomarker for PCa. qPCR miRNA expression profiling. mRNA from 10 Prostate Cancer patients (5 Caucasian American and 5 African American) and their paired adjacent normal tissue were analysed to identify the differentially expressed miRNA between the groups. Equal amount small RNA from each group was pooled prior to gene expression analysis.
2013-11-15 | E-GEOD-48430 | biostudies-arrayexpress
Project description:A comprehensive systemic assessment of the proteome changes that occur in prostate cancer (PCa) during the onset and course of the illness may produce results that are clinically significant. Proteins, the main participants in the majority of biological events, are both potential biomarkers and therapeutic targets. Although the PCa tissue proteome has already been described, screening tissue samples is an intrusive operation. As a result, we concentrated on liquid biopsies like urine samples for this investigation. Specifically, liquid chromatography coupled to high-resolution mass spectrometry (LC-MS/MS) was employed to examine the urinary small extracellular vesicle (EV) proteome patterns of 100 patients. The main objective of this study is to identify biomarkers for PCa patients with cribriform pattern and intraductal PCa (IDC).
2025-05-06 | PXD043874 | Pride
Project description:Background: Aldo-keto reductase (AKR) 1C family member 3 (AKR1C3), one of four identified human AKR enzymes, catalyzes steroid, prostaglandin, and xenobiotic metabolism. In the prostate, AKR1C3 is up-regulated in localized and advanced prostate adenocarcinoma, and is associated with prostate cancer (PCa) aggressiveness. Here we provide initial evidence for potential roles of AKR1C3 in PCa progression. Methods: Spatial distribution of AKR1C3 was analyzed using immunohistochemical staining in prostate adenocarcinoma tissue array. Human PCa PC-3 cells were stably transfected with AKR1C3 cDNA to establish PC3-AKR1C3 transfectants. Microarray and bioinformatics analyses were performed to identify pathways that are activated by elevated AKR1C3 expression in PCa cells. Functional confirmation of microarray and bioinformatics results was performed by immunoblot analysis and an in vitro Matrigel angiogenesis assay. Results: Elevated AKR1C3 expression was specifically limited to human prostate adenocarcinoma. Microarray and bioinformatics analysis suggested that elevated AKR1C3 expression in PC-3 cells modulates estradiol and androgen metabolism and activates insulin growth factor (IGF)-1 and Akt signaling pathways. Immunoblots confirmed that phosphorylated levels of IGF-1 receptor (IGF-1R) and Akt are significantly up-regulated in PC3-AKR1C3 as compared to mock transfectants. PC3-AKR1C3 transfectants promoted endothelial cell tube formation in Matrigel as compared to parental PC-3 cells and mock transfectants. Conclusion: Microarray and bioinformatics data followed by biological analyses suggest that elevated AKR1C3 expression in PC-3 cells promotes PCa angiogenesis and aggressiveness. These results suggest AKR1C3 can promote the aggressiveness of PCa through modulating estrogen and androgen metabolism with subsequent activation of growth factor IGF-1 and cytoplasmic Akt signaling pathways. Total RNA from mock- and ACR1C3 transfected PC-3 cells was isolated, with 2 or 3 biological replicates each. Gene expression data from AKR1C3 transfected PC-3 cells were compared with mock-transfected data.
2010-08-10 | E-GEOD-20956 | biostudies-arrayexpress
Project description:Extracellular vesicles (EVs) are membrane-encapsulated particles that vary greatly in size and content. Although both normal and tumor cells produce an array of small EVs (S-EVs), only tumor cells have been found to release a population of atypically large EVs (L-EVs), also known as large oncosomes (LO). Little is known about the cargo of L-EVs, and how it differs from the S-EVs. Given the potential for tumor-derived L-EVs to provide insights into disease mechanisms and course, we performed proteomic analysis of L- and S-EVs derived from three cancer models followed by comparative proteomic and transcriptomic analysis of EVs from the prostate cancer model. 1) We identified both common and model-specific protein signatures for L- and S-EVs. 2) A subset of the proteins enriched in prostate cancer cell-derived L-EVs were also identified in L-EVs isolated from plasma of patients with metastatic prostate cancer. 3) Proteins enriched in L-EV that were also identified at the transcript level were mostly mitochondrial in origin, as confirmed by single vesicle RNA-Seq. Additionally, the L-EV mitochondrial signature was detected in plasma-derived L-EVs and distinguished patients with prostate cancer from cancer-free individuals as well as patients with metastatic prostate cancer from those with localized disease, corroborating the relevance of an integrative multi-analyte approach focused on L-EVs for liquid biopsy.
2025-04-16 | GSE231846 | GEO