Combined inhibition of STAT and Notch signalling effectively suppresses tumourigenesis by inducing apoptosis and inhibiting proliferation, migration and invasion in glioblastoma cells.
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ABSTRACT:
SUBMITTER: Tulip IJ
PROVIDER: S-EPMC8253205 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Both betulinic acid (BA) and mithramycin A (MIT) exhibit potent antitumor activity through distinct mechanisms of Sp1 inhibition. However, it is unknown whether a combination of these two compounds results in a synergistic inhibitory effect on pancreatic cancer growth and/or has a therapeutic advantage over gemcitabine. In xenograft mouse models of human pancreatic cancer, treatment with either BA or MIT alone showed dose-dependent antitumor activity but led to systemic side effects as measured by overall weight loss. Treatment with a nontoxic dose of either compound alone had only marginal antitumor effects. Importantly, combination treatment with nontoxic doses of BA and MIT produced synergistic antitumor activity, including inhibitory effects on cell proliferation, invasion, and angiogenesis. The treatment combination also produced less discernible side effects than therapeutic doses of gemcitabine. Moreover, combined treatment of BA and MIT resulted in drastic inhibition of Sp1 recruitment onto Sp1 and VEGF promoters, leading to transcriptional inhibition of both Sp1 and VEGF and downregulation of Sp1 and VEGF protein expression. Ectopic overexpression of Sp1 rendered tumor cells resistant to BA, MIT, and the combination of the two. Overall, our findings argue that Sp1 is an important target of BA and MIT and that their combination can produce an enhanced therapeutic response in human pancreatic cancer.
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Project description:Metastasis is the major cause of cancer-related morbidity and mortality. The ability of cancer cells to become invasive and migratory contribute significantly to metastatic growth, which necessitates the identification of novel anti-migratory and anti-invasive therapeutic approaches. Proteoglycan 4 (PRG4), a mucin-like glycoprotein, contributes to joint synovial homeostasis through its friction-reducing and anti-adhesive properties. Adhesion to surrounding extracellular matrix (ECM) components is critical for cancer cells to invade the ECM and eventually become metastatic, raising the question whether PRG4 has an anti-invasive effect on cancer cells. Here, we report that a full-length recombinant human PRG4 (rhPRG4) suppresses the ability of the secreted protein transforming growth factor beta (TGFβ) to induce phenotypic disruption of three-dimensional human breast cancer cell-derived organoids by reducing ligand-induced cell invasion. In mechanistic studies, we find that rhPRG4 suppresses TGFβ-induced invasiveness of cancer cells by inhibiting the downstream hyaluronan (HA)-cell surface cluster of differentiation 44 (CD44) signalling axis. Furthermore, we find that rhPRG4 represses TGFβ-dependent increase in the protein abundance of CD44 and of the enzyme HAS2, which is involved in HA biosynthesis. It is widely accepted that TGFβ has both tumor suppressing and tumor promoting roles in cancer. The novel finding that rhPRG4 opposes HAS2 and CD44 induction by TGFβ has implications for downregulating the tumor promoting roles, while maintaining the tumor suppressive aspects of TGFβ actions. Finally, these findings point to rhPRG4's potential clinical utility as a therapeutic treatment for invasive and metastatic breast cancer.
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Project description:Purpose:MiR-654-3p plays important roles in many types of malignant tumours. However, the biological function of miR-654-3p in non-small cell lung cancer (NSCLC) remains unknown. In this study, the role of miR-654-3p in NSCLC was investigated. Methods:qRT-PCR was used to evaluate the level of miR-654-3p in NSCLC tissues and cell lines, while Cell Counting Kit-8, Annexin V/propidium iodide dual staining or TUNEL staining were used to investigate proliferation and apoptosis of NSCLC cells. Luciferase assays and Western blotting were performed to validate potential targets of miR-654-3p. Results:MiR-654-3p levels were significantly decreased in NSCLC patients and cell lines and were significantly correlated with the tumour size and tumour node metastasis stage of NSCLC patients. In A549 cells, miR-654-3p overexpression significantly increased apoptosis and inhibited growth both in vivo and in vitro, while downregulation of miR-654-3p had the opposite effects. In addition, polo-like kinase 4 (PLK4) was shown to be a target gene of miR-654-3p that is negatively regulated by miR-654-3p in A549 cells. Furthermore, PLK4 was observed to be highly expressed in NSCLC tissues and cells, and PLK4 overexpression abolished the inhibitory effects of miR-654-3p overexpression on NSCLC cell proliferation. Finally, the animal experiment results further demonstrated that miR-654-3p inhibits tumour growth and regulates PLK4 expression. Conclusion:Our results demonstrate that miR-654-3p functions as a growth-suppressing miRNA by targeting PLK4 in NSCLC.
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Project description:ObjectiveTofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated.MethodsA randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699).ResultsTofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo.ConclusionsTofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response.Trial registration numberNCT00976599.
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Project description:Inactivation of tumor suppressors and inhibitory microenvironmental factors is necessary for breast cancer invasion; therefore, identifying those suppressors and factors is crucial not only to advancing our knowledge of breast cancer, but also to discovering potential therapeutic targets. By analyzing gene expression profiles of polarized and disorganized human mammary epithelial cells in a physiologically relevant three-dimensional (3D) culture system, we identified retinoid orphan nuclear receptor alpha (ROR?) as a transcription regulator of semaphorin 3F (SEMA3F), a suppressive microenvironmental factor. We showed that expression of ROR? was downregulated in human breast cancer tissue and cell lines, and that reduced mRNA levels of ROR? and SEMA3F correlated with poor prognosis. Restoring ROR? expression reprogrammed breast cancer cells to form noninvasiveness structures in 3D culture and inhibited tumor growth in nude mice, accompanied by enhanced SEMA3F expression. Inactivation of ROR? in nonmalignant human mammary epithelial cells inhibited SEMA3F transcription and impaired polarized acinar morphogenesis. Using chromatin immunoprecipitation and luciferase reporter assays, we showed that transcription of SEMA3F is directly regulated by ROR?. Knockdown of SEMA3F in ROR?-expressing cancer cells rescued the aggressive 3D phenotypes and tumor invasion. These findings indicate that ROR? is a potential tumor suppressor and inhibits tumor invasion by inducing suppressive cell microenvironment.
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Project description:BackgroundNasopharyngeal carcinoma (NPC) is especially prevalent in southeast Asia and southern China, but its molecular mechanisms remain poorly characterized. DNA methylation is associated with initiation and progression of tumors, including NPC. Through a genome-wide DNA methylation screening approach, we discovered ZNF154, but its methylation status and roles in NPC have not been investigated.MethodsThe methylation status of ZNF154 in NPC was detected with Methylation specific-PCR (MSP) and Quantitative Sequenom MassARRAY. The invasion and migration capacities were examined by wound healing and transwell invasion assays. The role of ZNF154 in NPC metastasis was clarified with experimental metastasis assay in vivo. Western blotting analysis was used to investigate protein changes followed by ZNF154 over-expression. Kaplan-Meier analysis was performed to determine the association between ZNF154 methylation and prognosis in NPC.ResultsCompared to immortalized nasopharyngeal tissues and cells, ZNF154 expression was frequently downregulated in NPC tissues and cell lines due to promoter methylation. Demethylation treatment with 5-aza-2-deoxycytidine (5-Aza) restored ZNF154 expression in NPC cell lines. Ectopic overexpression of ZNF154 in NPC cells inhibited cell migration and invasion in vitro and lung nodule formation in an in vivo tumor metastasis assay. Mechanistic investigations suggested ZNF154 inhibits Wnt/β-catenin signalling pathway activation and prevents the EMT in NPC. Furthermore, Kaplan-Meier analysis showed hypermethylation of the ZNF154 promoter was associated with significantly poorer disease-free survival (P = 0.032) and distant metastasis-free survival (P = 0.040) among patients with locoregionally advanced NPC.ConclusionsTaken together, these findings define a novel role for ZNF154 as a tumor suppressor in NPC.
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Project description:Interferon regulatory factor 8 (IRF8) is known to affect the innate immune response, for example, by regulating the differentiation and function of immune cells. However, whether IRF8 can influence cardiac hypertrophy is unknown. Here we show that IRF8 levels are decreased in human dilated/hypertrophic cardiomyopathic hearts and in murine hypertrophic hearts. Mice overexpressing Irf8 specifically in the heart are resistant to aortic banding (AB)-induced cardiac hypertrophy, whereas mice lacking IRF8 either globally or specifically in cardiomyocytes develop an aggravated phenotype induced by pressure overload. Mechanistically, we show that IRF8 directly interacts with NFATc1 to prevent NFATc1 translocation and thus inhibits the hypertrophic response. Inhibition of NFATc1 ameliorates the cardiac abnormalities in IRF8(-/-) mice after AB. In contrast, constitutive activation of NFATc1 nullifies the protective effects of IRF8 on cardiac hypertrophy in IRF8-overexpressing mice. Our results indicate that IRF8 is a potential therapeutic target in pathological cardiac hypertrophy.
| S-EPMC3929801 | biostudies-literature
Project description:Influenza A virus (IAV) polymerase protein PB2 has been shown to partially inhibit the host immune response by blocking the induction of interferons (IFNs). However, the IAV PB2 protein that regulates the downstream signaling pathway of IFNs is not well characterized. Here, we report that IAV PB2 protein reduces cellular sensitivity to IFNs, suppressing the activation of STAT1/STAT2 and ISGs. Furthermore, IAV PB2 protein targets mammalian JAK1 at lysine 859 and 860 for ubiquitination and degradation. Notably, the H5 subtype of highly pathogenic avian influenza virus with I283M/K526R mutations on PB2 increases the ability to degrade mammalian JAK1 and exhibits higher replicate efficiency in mammalian (but not avian) cells and mouse lung tissues, and causes greater mortality in infected mice. Altogether, these data describe a negative regulatory mechanism involving PB2-JAK1 and provide insights into an evasion strategy from host antiviral immunity employed by IAV.
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Project description:Macrophages within adipose tissue play a key role in mediating inflammatory responses in adipose tissue that are associated with obesity-related metabolic complications. In an effort to identify novel proteins secreted from adipocytes that may negatively regulate macrophage inflammation, we found that peroxiredoxin (PRX)-like 2 activated in M-CSF stimulated monocytes (PAMM), a CXXC-type PRX-like 2 domain-containing redox regulatory protein, is a novel secreted protein with potent anti-inflammatory properties. PAMM is secreted from mature human adipocytes but not preadipocytes. Overexpression of PAMM significantly attenuated lipopolysaccharide (LPS)-induced macrophage inflammation. Incubation of macrophages with adipocyte-conditional medium treated with anti-PAMM antibody significantly enhanced LPS-induced interleukin-12 (IL-12) expression in Raw264.7 cells. In addition, incubation of Raw264.7 cells with purified PAMM protein had a similar anti-inflammatory effect. Moreover, forced expression of PAMM in Raw264.7 cells resulted in decreased LPS-induced ERK1/2, p38 and c-Jun N-terminal kinase (JNK) phosphorylation, suggesting that PAMM exerted the anti-inflammatory function probably by suppressing the mitogen-activated protein kinase (MAPK) signalling pathway. Mutations in the CXXC motif of PAMM that suppressed its anti-redox activity were still able to suppress production of inflammatory cytokines in LPS-stimulated macrophages, suggesting that PAMM's anti-inflammatory properties may be independent of its antioxidant properties. Finally, PAMM was highly expressed in both white (WAT) and brown adipose tissues (BAT) and further increased in obesity status. Our results suggest that adipocyte-derived PAMM may suppress macrophage activation by inhibiting MAPK signalling pathway.
| S-EPMC4754088 | biostudies-literature
Project description:Background and purposeAngiogenesis contributes to coronary heart disease, immune disorders and numerous malignancies. VEGF-A and its receptors (VEGFRs) play a pivotal role in regulating angiogenesis. In an effort to discover more effective inhibitors of tumour angiogenesis, we have analysed the actions of a novel anthraquinone derivative, PPemd26, and explored its anti-angiogenic mechanisms.Experimental approachThe effects of PPemd26 were evaluated in vitro using HUVEC cultures to assess proliferation, migration, invasion and tube formation. Immunoblotting was used to analyse phosphorylation of signalling kinases. Effects in vivo were assayed using Matrigel plug and xenograft mouse models.Key resultsPPemd26 significantly inhibited VEGF-A-induced proliferation, migration, invasion and tube formation of HUVECs. PPemd26 also attenuated VEGF-A-induced microvessel sprouting from rat aortic rings ex vivo and suppressed formation of new blood vessels in implanted Matrigel plugs in models of angiogenesis in vivo. In addition, PPemd26 inhibited VEGF-A-induced phosphorylation of VEGFR2 and its downstream protein kinases including Akt, focal adhesion kinase, ERK and Src. Furthermore, systemic administration of PPemd26 suppressed the growth of s.c. xenografts of human colon carcinoma in vivo. Histochemical analysis of the xenografts revealed a marked reduction in stainingfor the vascular marker CD31 and proliferation marker Ki-67.Conclusions and implicationsThis study provides evidence that PPemd26 suppressed tumour angiogenesis through inhibiting VEGFR2 signalling pathways, suggesting that PPemd26 is a potential drug candidate for developing anti-angiogenic agents for the treatment of cancer and angiogenesis-related diseases.
| S-EPMC4290713 | biostudies-literature