STAMP2 Expression Mediated by Cytokines Attenuates Their Growth-Limiting Effects in Prostate Cancer Cells.
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ABSTRACT:
SUBMITTER: Pihlstrom N
PROVIDER: S-EPMC8036285 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Ursodeoxycholic acid (UDCA) is one of the first-line therapeutic medications used in treatment of cholestatic liver disease. Considering that periodontitis is epidemiologically linked to liver diseases, the question arises weather UDCA holds anti-inflammatory properties on periodontal health. Herein, we provide information that support anti-inflammatory effects of UDCA on three different periodontium-related cell types. Gingival fibroblasts and the oral human squamous carcinoma cell line HSC-2 were exposed to interleukin (IL)1β and tumor necrosis factor (TNF)α with and without UDCA. Murine RAW 264.7 macrophages were incubated with sterile-filtered human saliva also in the presence of UDCA. The expression of inflammatory cytokines was measured by reverse transcription-polymerase chain reaction. Immunoassay was applied to detect the production of IL6. Immunostaining was performed for the p65 subunit to further support the anti-inflammatory role of UDCA. We report here that UDCA significantly reduced the IL1β and TNFα-induced expression of IL1, IL6, and IL8 in gingival fibroblasts and the HSC-2 cell line. In RAW 264.7 macrophages, UDCA attenuated the expression of IL1α, IL1β, and IL6 that was increased by saliva. Immunoassay confirmed the capacity of UDCA to reduce inflammation-induced production of IL6 in gingival fibroblasts, HSC-2 and RAW 264.7 cells. Immunostaining revealed the blocking of nuclear translocation of p65 in gingival fibroblasts. Taken together, UDCA can attenuate the provoked expression of inflammatory cytokines in oral fibroblasts, oral human squamous carcinoma cells and macrophages in vitro. These data support the hypothesis that patients with cholestatic liver disease might benefit from UDCA with respect to periodontal health.
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Project description:The DKK3 gene encodes a secreted protein, Dkk-3, that inhibits prostate tumor growth and metastasis. DKK3 is downregulated by promoter methylation in many types of cancer, including prostate cancer. Gene silencing studies have shown that Dkk-3 maintains normal prostate epithelial cell homeostasis by limiting TGF-?/Smad signaling. While ectopic expression of Dkk-3 leads to prostate cancer cell apoptosis, it is unclear if Dkk-3 has a physiological role in cancer cells. Here, we show that treatment of PC3 prostate cancer cells with the DNA methyltransferase (DNMT) inhibitor decitabine demethylates the DKK3 promoter, induces DKK3 expression, and inhibits TGF-?/Smad-dependent transcriptional activity. Direct induction of DKK3 expression using CRISPR-dCas9-VPR also inhibited TGF-?/Smad-dependent transcription and attenuated PC3 cell migration and proliferation. These effects were not observed in C4-2B cells, which do not respond to TGF-?. TGF-? signals can regulate gene expression directly via SMAD proteins and indirectly by increasing DNMT expression, leading to promoter methylation. Analysis of genes downregulated by promoter methylation and predicted to be regulated by TGF-? found that DKK3 induction increased expression of PTGS2, which encodes cyclooxygenase-2. Together, these observations provide support for using CRISPR-mediated induction of DKK3 as a potential therapeutic approach for prostate cancer and highlight complexities in Dkk-3 regulation of TGF-? signaling.
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Project description:The six transmembrane protein of prostate 2 (STAMP2) is an androgen-regulated gene whose mRNA expression is increased in prostate cancer (PCa). Here, we show that STAMP2 protein expression is increased in human PCa compared with benign prostate that is also correlated with tumor grade and treatment response. We also show that STAMP2 significantly increased reactive oxygen species (ROS) in PCa cells through its iron reductase activity which also depleted NADPH levels. Knockdown of STAMP2 expression in PCa cells inhibited proliferation, colony formation, and anchorage-independent growth, and significantly increased apoptosis. Furthermore, STAMP2 effects were, at least in part, mediated by activating transcription factor 4 (ATF4), whose expression is regulated by ROS. Consistent with in vitro findings, silencing STAMP2 significantly inhibited PCa xenograft growth in mice. Finally, therapeutic silencing of STAMP2 by systemically administered nanoliposomal siRNA profoundly inhibited tumor growth in two established preclinical PCa models in mice. These data suggest that STAMP2 is required for PCa progression and thus may serve as a novel therapeutic target.
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Project description:Six Transmembrane Protein of Prostate 2 (STAMP2) has been implicated in both prostate cancer (PCa) and metabolic disease. STAMP2 has unique anti-inflammatory and pro-metabolic properties in mouse adipose tissue, but there is limited information on its role in human metabolic tissues. Using human adipose-derived stem cells (ASCs), we report that STAMP2 expression is dramatically upregulated during adipogenesis. shRNA-mediated STAMP2 knockdown in ASCs significantly suppresses adipogenesis and interferes with optimal expression of adipogenic genes and adipocyte metabolic function. Furthermore, ASC-derived adipocyte-mediated stimulation of prostate tumor growth in nude mice is significantly reduced upon STAMP2 knockdown in ASC adipocytes. These results suggest that STAMP2 is crucial for normal ASC conversion into adipocytes and their metabolic function, as well as their ability to facilitate PCa growth in vivo.
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Project description:White button mushroom (WBM) is a common edible mushroom consumed in the United States and many European and Asia-Pacific countries. We previously reported that dietary WBM antagonized dihydrotestosterone (DHT)-induced androgen receptor (AR) activation and reduced myeloid-derived suppressor cells (MDSCs) in prostate cancer animal models and patients. Transmembrane protease serine 2 (TMPRSS2), an androgen-induced protease in prostate cancer, has been implicated in influenza and coronavirus entry into the host cell, triggering host immune response. The present study on C57BL/6 mice revealed that WBM is a unique functional food that (A) interrupts AR-mediated TMPRSS2 expression in prostate, lungs, small intestine, and kidneys through its AR antagonistic activity and (B) attenuates serum pro-inflammatory cytokines and reduces MDSC counts through its immunoregulatory activity. These findings provide a scientific basis for translational studies toward clinical applications of WBM in diseases related to TMPRSS2 expression and immune dysregulation.
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Project description:OBJECTIVE:Cell density in tumor cell three dimensional (3D) cultures affects secretome expression of components. A microenvironment characteristic shared by high-density 3D cell culture and in vivo tumor masses is poor oxygenation, with anoxia being a natural cell state in tumor centers. Until recently, the ability to study anoxia-adapted cell physiology was not possible. Using a newly-developed methodology, anoxic HeLa cell secretome expression was measured. RESULTS:Anoxic HeLa cell cytokine levels after 3 days' (hypoxia inducible factor, HIF1 positive) and 10 days' growth (HIF1 negative; anaerobic respiration) were significantly (p?<?0.01) higher than normoxic controls for: IL-8 (1.8- and 3.4-fold higher, respectively), GRO (1.3- and 1.1-fold higher, respectively), and IL-11 (1.4- and 1.1-fold higher, respectively). In contrast, G-CSF, IFN?2, and CXCL-10 levels decreased over time (day 3 vs. day 10). Thus, metabolically active HeLa cells respond to the lack of oxygen, in part, by regulating the levels of cytokines produced. Cytokines expressed at increased levels, in the absence of oxygen, correspond to a secretomic profile reported for paracrine signaling pathways associated with metastasis. Further studies defining physiologic changes that occur upon anoxic growth may lead to the discovery of novel chemotherapeutic drug targets.
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Project description:BACKGROUND:Dysregulation of microRNA (miRNA) expression is associated with hallmarks of aggressive tumor phenotypes, e.g., enhanced cell growth, proliferation, invasion, and anchorage independent growth in prostate cancer (PCa). METHODS:Serum-based miRNA profiling involved 15 men diagnosed with non-metastatic (stage I, III) and metastatic (stage IV) PCa and five age-matched disease-free men using miRNA arrays with select targets confirmed by quantitative real-time PCR (qRT-PCR). The effect of miR-186-5p inhibition or ectopic expression on cellular behavior of PCa cells (i.e., PC-3, MDA-PCa-2b, and LNCaP) involved the use bromodeoxyuridine (BrdU) incorporation, invasion, and colony formation assays. Assessment of the impact of miR-186-5p inhibition or overexpression on selected targets entailed microarray analysis, qRT-PCR, and/or western blots. Statistical evaluation used the modified t-test and ANOVA analysis. RESULTS:MiR-186-5p was upregulated in serum from PCa patients and metastatic PCa cell lines (i.e., PC-3, MDA-PCa-2b, LNCaP) compared to serum from disease-free individuals or a normal prostate epithelial cell line (RWPE1), respectively. Inhibition of miR-186-5p reduced cell proliferation, invasion, and anchorage-independent growth of PC-3 and/or MDA-PCa-2b PCa cells. AKAP12, a tumor suppressor target of miR-186-5p, was upregulated in PC-3 and MDA-PCa-2b cells transfected with a miR-186-5p inhibitor. Conversely, ectopic miR-186-5p expression in HEK 293 T cells decreased AKAP12 expression by 30%. Both pAKT and ?-catenin levels were down-regulated in miR-186-5p inhibited PCa cells. CONCLUSIONS:Our findings suggest miR-186-5p plays an oncogenic role in PCa. Inhibition of miR-186-5p reduced PCa cell proliferation and invasion as well as increased AKAP12 expression. Future studies should explore whether miR-186-5p may serve as a candidate prognostic indicator and a therapeutic target for the treatment of aggressive prostate cancer.
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Project description:In response to environmental cues that promote IP3 (inositol 1,4,5-trisphosphate) generation, IP3 receptors (IP3Rs) located on the endoplasmic reticulum allow the 'quasisynaptical' feeding of calcium to the mitochondria to promote oxidative phosphorylation. However, persistent Ca2+ release results in mitochondrial Ca2+ overload and consequent apoptosis. Among the three mammalian IP3Rs, IP3R3 appears to be the major player in Ca2+-dependent apoptosis. Here we show that the F-box protein FBXL2 (the receptor subunit of one of 69 human SCF (SKP1, CUL1, F-box protein) ubiquitin ligase complexes) binds IP3R3 and targets it for ubiquitin-, p97- and proteasome-mediated degradation to limit Ca2+ influx into mitochondria. FBXL2-knockdown cells and FBXL2-insensitive IP3R3 mutant knock-in clones display increased cytosolic Ca2+ release from the endoplasmic reticulum and sensitization to Ca2+-dependent apoptotic stimuli. The phosphatase and tensin homologue (PTEN) gene is frequently mutated or lost in human tumours and syndromes that predispose individuals to cancer. We found that PTEN competes with FBXL2 for IP3R3 binding, and the FBXL2-dependent degradation of IP3R3 is accelerated in Pten-/- mouse embryonic fibroblasts and PTEN-null cancer cells. Reconstitution of PTEN-null cells with either wild-type PTEN or a catalytically dead mutant stabilizes IP3R3 and induces persistent Ca2+ mobilization and apoptosis. IP3R3 and PTEN protein levels directly correlate in human prostate cancer. Both in cell culture and xenograft models, a non-degradable IP3R3 mutant sensitizes tumour cells with low or no PTEN expression to photodynamic therapy, which is based on the ability of photosensitizer drugs to cause Ca2+-dependent cytotoxicity after irradiation with visible light. Similarly, disruption of FBXL2 localization with GGTi-2418, a geranylgeranyl transferase inhibitor, sensitizes xenotransplanted tumours to photodynamic therapy. In summary, we identify a novel molecular mechanism that limits mitochondrial Ca2+ overload to prevent cell death. Notably, we provide proof-of-principle that inhibiting IP3R3 degradation in PTEN-deregulated cancers represents a valid therapeutic strategy.
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Project description:The trace element fluoride can be beneficial for oral health by preventing dental caries. However, fluoride is also known as an environmental pollutant. Fluoride pollution can lead to fluoride over-ingestion and can cause health issues, including dental fluorosis. Curcumin attenuated fluoride-induced toxicity in animal models, however the molecular mechanisms of how curcumin affects fluoride toxicity remain to be elucidated. We hypothesized that curcumin attenuates fluoride toxicity through modulation of Ac-p53. Here we investigated how curcumin affects the p53-p21 pathway in fluoride toxicity. LS8 cells were treated with NaF with/without curcumin. Curcumin significantly increased phosphorylation of Akt [Thr308] and attenuated fluoride-mediated caspase-3 cleavage and DNA damage marker γH2AX expression. Curcumin-mediated attenuation of caspase-3 activation was reversed by Akt inhibitor LY294002 (LY). However, LY did not alter curcumin-mediated γH2AX suppression. These results suggest that curcumin inhibited fluoride-mediated apoptosis via Akt activation, but DNA damage was suppressed by other pathways. Curcumin did not suppress/alter fluoride-mediated Ac-p53. However, curcumin itself significantly increased Ac-p53 and upregulated p21 protein levels to suppress cell proliferation in a dose-dependent manner. Curcumin suppressed fluoride-induced phosphorylation of p21 and increased p21 levels within the nuclear fraction. However, curcumin did not reverse fluoride-mediated cell growth inhibition. These results suggest that curcumin-induced Ac-p53 and p21 led to cell cycle arrest, while curcumin attenuated fluoride-mediated apoptosis via activation of Akt and suppressed fluoride-mediated DNA damage. By inhibiting DNA damage and apoptosis, curcumin may potentially alleviate health issues caused by fluoride pollution. Further studies are required to better understand the mechanism of curcumin-induced biological effects on fluoride toxicity.
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