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A novel action mechanism for MPT0G013, a derivative of arylsulfonamide, inhibits tumor angiogenesis through up-regulaiton of TIMP3 expression

ABSTRACT: Tissue inhibitors of metalloproteinases 3 (TIMP3) were originally characterized as inhibitors of matrix metalloproteinases (MMPs), acting as potent antiangiogenic proteins. In this study, we demonstrated that the arylsulfonamide derivative MPT0G013 has potent antiangiogenic activities in vitro and in vivo via inducing TIMP3 expression. Treatments with MPT0G013 significantly inhibited endothelial cell functions, such as cell proliferation, migration, and tube formation, as well as induced p21 and cell cycle arrest at the G0/G1 phase. Subsequent microarray analysis showed significant induction of TIMP3 gene expression by MPT0G013, and siRNA-mediated blockage of TIMP3 up-regulation abrogated the antiangiogenic activities of MPT0G013 and prevented inhibition of p-AKT and p-ERK proteins. Importantly, MPT0G013 exhibited antiangiogenic activities in in vivo Matrigel plug assays, inhibited tumor growth and up-regulated TIMP3 and p21 proteins in HCT116 mouse xenograft models. These data suggest potential therapeutic application of MPT0G013 for angiogenesis-related diseases such as cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE56927 | GEO | 2017/02/09

SECONDARY ACCESSION(S): PRJNA244974

REPOSITORIES: GEO

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TIMP2 and TIMP3 have divergent roles in early renal tubulointerstitial injury

Project description:Tissue inhibitors of metalloproteinases (TIMP) are endogenous inhibitors of matrix metalloproteinases (MMP). While TIMP2 and TIMP3 inhibit MMPs, TIMP3 also inhibits activation of pro-MMP2 whereas TIMP2 promotes it. Here we assessed the differential role of TIMP2 and TIMP3 in renal injury using the unilateral ureteral obstruction model. Gene microarray assay showed that post-obstruction, the lack of TIMP3 had a greater impact on gene expression of intermediate, late injury- and repair-induced transcripts, kidney selective transcripts and solute carriers. Renal injury in TIMP3-/-, but not in TIMP2-/- mice increased expression of collagen type I/III, connective tissue growth factor, transforming growth factor-Î² and the downstream Smad2/3 pathway. Interestingly, ureteral obstruction markedly increased MMP2 activation in the kidneys of TIMP3-/- mice which was completely blocked in the kidneys of TIMP2-/- mice. These changes are consistent with enhanced renal tubulointerstitial fibrosis in TIMP3-/- and its reduction in TIMP2-/- mice. The activity of tumor necrosis factor-Î± converting enzyme, caspase-3 and mitogen activated kinases were elevated in the kidneys of TIMP3-/- but not TIMP2-/- mice, suggesting enhanced activation of apoptotic and pathological signaling pathways only in the obstructed kidney of TIMP3-/- mice. Thus, TIMP2 and TIMP3 play differential and contrasting roles in renal injury, TIMP3 protects from damage whereas TIMP2 promotes injury through MMP2 activation. Kidneys from the wild type (WT), TIMP2-/- and TIMP3-/- mice undergoing sham or unilateral ureteral obstruction (UUO) procedures

2013-07-01 | E-GEOD-42303 | biostudies-arrayexpress

TIMP2 and TIMP3 have divergent roles in early renal tubulointerstitial injury

Project description:Tissue inhibitors of metalloproteinases (TIMP) are endogenous inhibitors of matrix metalloproteinases (MMP). While TIMP2 and TIMP3 inhibit MMPs, TIMP3 also inhibits activation of pro-MMP2 whereas TIMP2 promotes it. Here we assessed the differential role of TIMP2 and TIMP3 in renal injury using the unilateral ureteral obstruction model. Gene microarray assay showed that post-obstruction, the lack of TIMP3 had a greater impact on gene expression of intermediate, late injury- and repair-induced transcripts, kidney selective transcripts and solute carriers. Renal injury in TIMP3-/-, but not in TIMP2-/- mice increased expression of collagen type I/III, connective tissue growth factor, transforming growth factor-β and the downstream Smad2/3 pathway. Interestingly, ureteral obstruction markedly increased MMP2 activation in the kidneys of TIMP3-/- mice which was completely blocked in the kidneys of TIMP2-/- mice. These changes are consistent with enhanced renal tubulointerstitial fibrosis in TIMP3-/- and its reduction in TIMP2-/- mice. The activity of tumor necrosis factor-α converting enzyme, caspase-3 and mitogen activated kinases were elevated in the kidneys of TIMP3-/- but not TIMP2-/- mice, suggesting enhanced activation of apoptotic and pathological signaling pathways only in the obstructed kidney of TIMP3-/- mice. Thus, TIMP2 and TIMP3 play differential and contrasting roles in renal injury, TIMP3 protects from damage whereas TIMP2 promotes injury through MMP2 activation.

2013-07-01 | GSE42303 | GEO

Transcriptomic landscape of TIMP3 oncosuppressor activity in thyroid carcinoma

Project description:In thyroid tumors TIMP3 methylation, and hence its downregulation, has been reported (Hoque MO et al, J Clin Endocrinol Metabolism 2005) and also found significantly associated with several aggressive features of PTC, including extrathyroidal invasion, lymph node metastasis, multifocality, advanced tumor stages and BRAF mutation (Hu S et al, Int J Cancer 2006). In a previous work, in addition to confirming TIMP3 downregulation in a consistent fraction of PTC, we evaluated the functional consequences of TIMP3 downregulation in a PTC-derived cell line model. We found that TIMP3 restoration in NIM1 cell line, in which the expression of TIMP3 is silenced by promoter hypermethylation, reduced in vitro migration, invasion and anchorage-independent growth. Using a mouse xenograft model we demonstrated that restoration of TIMP3 activity reduces tumor growth, concomitantly with reduction of angiogenesis and macrophage recruitment at tumor site (Anania et al, Oncogene 2011). Papillary thyroid cancer (PTC) is the most frequent thyroid tumor. The tissue inhibitor of metalloproteinase-3 (TIMP3) gene encodes a matrix metalloproteinases inhibitor that exerts a tumor suppressor role in several tumor types. TIMP3 is frequently downregulated in PTC by promoter methylation. We have previously functionally demonstrated that TIMP3 exerts an oncosuppressor role in PTC: TIMP3 restoration in the PTC-derived NIM1 cell line affects in vitro migration, invasion and adhesive capability, while reduces tumor growth, angiogenesis and macrophage recruitment in vivo. To have a broader view on the mediators of TIMP3 oncosuppressor activity in thyroid tumors, here we focused on the TIMP3 related transcriptome.By interrogating the TCGA data set and performing a genome-wide expression analysis of NIM1 cell line TIMP3 in vitro model, we show that different expression levels of TIMP3 lead to transcriptional changes that modulate, among other, inflammatory functions.

2022-12-21 | GSE206915 | GEO

The TIMP3/Apelin axis Regulates Atherosclerosis and Heart Metabolism leading to increased mortality in ApoE null Mice

Project description:The role of TIMP3 in the context of cardiovascular remodeling is relatively unexplored when considering classical risk factors such as hypercholesterolemia, diabetes and hypertension. To learn more the role of TIMP3 in the progression of cardiovascular disease we combined genetics, metabolomics and in vivo phenotypical analysis using the hypercholesterolemic ApoE null mice to generate ApoE-/-Timp3-/- mice, the latter showing increased atherosclerosis, increased mortality and arrhythmias compared to ApoE-/- mice. We have previously described Timp3-/-mice in ( Fiorentino, L., et al., Regulation of TIMP3 in diabetic nephropathy: a role for microRNAs. Acta Diabetol, 2013) . To generate ApoE-/-Timp3-/- knockout animals we crossbred the 2 strains. Offsprings were then backcrossed into ApoE animals for 6 generations to generate a pure lineage. Collectively, metabolite profiles, gene and protein expression consistently suggested a role for TIMP3 to underlie a decreased activation of PPARα/AMPK to dampen fatty acids β-oxidation eventually leading to atherosclerotic plaque composition vulnerability and perturbation of heart metabolism. mRNA profiling in ApoE-/-Timp3-/- mice revealed a TIMP3 effect to regulate Apelin, which we found decreased in the circulation due to its specific downregulation at the myocardial level but not in other well known sites of expression such as the adipose tissue. mRNA sequencing of the heart of ApoE-/-Timp3-/- mice vs ApoE-/- littermates controls.

2015-01-01 | E-GEOD-53548 | biostudies-arrayexpress

The TIMP3/Apelin axis Regulates Atherosclerosis and Heart Metabolism leading to increased mortality in ApoE null Mice

2015-01-01 | GSE53548 | GEO

GATA6 induces cell senescence to exerts lung cancer suppressive function and denotes a therapeutic opportunity for GATA6 deficient lung cancer patients

Project description:Lung cancer is the world-wide leading cause of cancer related deaths. Tumor suppressor genes (TSGs) play a critical role in restricting tumorigenesis and impact the therapeutic effect of various treatments. However, TSGs remain to be systemically determined in lung cancer. Here we identified GATA6 as a potent lung cancer TSG. GATA6 inhibited lung cancer cell growth in vitro and tumorigenesis in vivo. Mechanistically, GATA6 upregulated p53 expression to transcribe p21 mRNA while inhibited Akt activation to stabilize p21 protein, thus inducing lung cancer cell senescence. Furthermore, we showed that ectopic expression of GATA6 led to dramatic shrinkage of established lung tumor in vivo

2020-03-25 | GSE147447 | GEO

Loss of Musashi-1 inhibits breast cancer metastasis via regulation of Timp3/Mmp9

Project description:Loss of Musashi-1 inhibits breast cancer metastasis via regulation of Timp3/Mmp9

| PRJNA623199 | ENA

Homo sapiens

Project description:Antiangiogenic Antithrombin

| PRJNA94209 | ENA

Ciliary Hedgehog signaling restricts injury-induced adipogenesis

Project description:Injured skeletal muscle regenerates, but with age or in muscular dystrophies, muscle is replaced by fat. Upon injury, muscle-resident fibro/adipogenic progenitors (FAPs) proliferated and gave rise to adipocytes. These FAPs dynamically produced primary cilia, structures that transduce intercellular cues such as Hedgehog (Hh) signals. Genetically removing cilia from FAPs inhibited intramuscular adipogenesis, both after injury and in a mouse model of Duchenne muscular dystrophy. Blocking FAP ciliation also enhanced myofiber regeneration after injury and reduced myofiber size decline in the muscular dystrophy model. Hh signaling through FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis. A pharmacological mimetic of TIMP3 blocked the conversion of FAPs into adipocytes, pointing to a strategy to combat fatty degeneration of skeletal muscle. We conclude that ciliary Hh signaling by FAPs orchestrates the regenerative response to skeletal muscle injury.

2017-07-13 | GSE86073 | GEO

Heparan sulfate modifications of betaglycan promote TIMP3-dependent ectodomain shedding to fine-tune TGF-β signaling.

Project description:Betaglycan/type III TGF-β receptor (TGFBR3) is an established co-receptor for the TGF-β superfamily with direct binding demonstrated for TGF-β 1-3 and inhibin A. Betaglycan can be membrane-bound or have its ectodomain cleaved/ shed to produce soluble-betaglycan that has been demonstrated to sequester ligands. Extracellular domain of betaglycan is modified with glycosaminoglycan chains at Ser residues S534 and S545, to which heparan sulfate and chondroitin sulfate chains are covalently attached. To delineate the contribution of the heparan and chondroitin sulfate modifications on betaglycan on its shedding and thereby on TGF-β signaling in ovarian cancer biology, we used mutants of betaglycan with alterations to the different glycosaminoglycan modifications. We made the unexpected discovery that the heparan sulfate modifications are essential for maximum ectodomain shedding of betaglycan, which is further essential for the ability of betaglycan to suppress TGF-β signaling and the tumor cells responses to exogenous TGF-β ligand. Using unbiased transcriptomics, we identified TIMP3 as a key regulator of betaglycan shedding and thereby TGF-β signaling. Taken together, these studies are the first to demonstrate a critical link between the well-known modifications on betaglycan and TGF-β signaling responses.

2024-02-21 | GSE237403 | GEO

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