Invasion Of U87MG Cells Research Articles

Evaluation of anti-angiogenic agent F16 for targeting glioblastoma xenograft tumors

Glioblastoma Multiforme (GBM) is one of the most aggressive and lethal types of all cancers, with an average 5-year survival rate of 5%. Since GBM tumors are highly vascularized tumors, and their growth is angiogenesis-dependent, antagonizing tumor angiogenesis by using angiogenesis inhibitors were considered as one of the promising approaches. In this context, intensive preclinical evaluation of a novel small molecule named F16 has exhibited potent anti-angiogenic and anti-tumor activities by selectively antagonizing Vascular Endothelial Growth Factor Receptor (VEGFR). Also, recent pharmacokinetic evaluation of F16 with tissue distribution analysis has shown that this molecule is transported across the blood-brain barrier (BBB) and accumulates in the brain regions with no signs of neurotoxicity. Therefore, further studies were conducted to determine the efficacy of F16 in delaying glioblastoma progression via inhibiting tumor angiogenesis. Our in vitro studies have clearly demonstrated the ability of F16 to inhibit migration and invasion of U87MG cells and also confirmed a potent cytotoxic effect against these cells in comparison to Temozolomide (TMZ). Our in vivo studies with the subcutaneously implanted (s.c.) xenograft tumor model and in vitro studies have clearly demonstrated the ability of F16 to delay tumor growth and inhibit migration and invasion.

Synthesis and evaluation of the epithelial-to- mesenchymal inhibitory activity of indazole-derived imidazoles as dual ALK5/p38α MAP inhibitors.

Drugs of targeting both activin receptor-like kinase 5 (ALK5) and p38α have therapeutic advantages, making them attractive treatment options for tumors. Two series of 4-(1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazoles 13a-g and 4-(1-methyl-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazoles 20a-g were synthesized and evaluated for ALK5 and p38α mitogen-activated protein kinase inhibitory activity. The most potent compound, 13c (J-1090), inhibited ALK5- and p38α-mediated phosphorylation with half-maximal inhibitor concentrations of 0.004μM and 0.004μM, respectively, in the enzymatic assay. In this study, the effectiveness of 13c in transforming growth factor (TGF-β)-exposed U87MG cells was investigated using western blotting, immunofluorescence assays, cell migration assay, invasion assay, and RT-PCR analysis. 13c inhibited the protein expression of Slug and the protein and RNA expression of the mesenchymal-related proteins N-cadherin and vimentin. Furthermore, 13c markedly suppressed TGF-β-induced epithelial-to-mesenchymal transition (EMT), migration, and invasion in U87MG cells. These results suggest that 13c is a novel inhibitor of ALK5 with potential utility in the treatment of human glioma.

GOLPH3 Promotes Vasculogenic Mimicry via the Epithelial Mesenchymal Transition in Glioblastoma Cells.

To evaluate the relationship between Golgi phosphoprotein 3 (GOLPH3) and vasculogenic mimicry (VM) in glioblastoma cells. Glioma tissues from 40 glioma patients with different pathological grades were collected. GOLPH3 and VM were evaluated by immunostaining in glioma tissues. Then, the correlation between GOLPH3 and VM were analyzed clinically. Additionally, a GOLPH3-downregulation lentivirus was constructed and transfected into the human primary glioblastoma cell line, U-87 MG. Afterwards, apoptosis, migration and invasion were assessed to determine the effects of downregulation GOLPH3. Then, E-cadherin and matrix metalloproteinase 2 (MMP2) were detected for assessment of the epithelial mesenchymal transition (EMT). GOLPH3 and VM were found to be positively correlated following clinical analysis (p < 0.01, r=0.788). Furthermore, GOLPH3 downregulation suppressed the migration and invasion of U87 MG cells (p < 0.05), followed by upregulation of E-cadherin and downregulation of MMP2. Collectively, our results demonstrate that GOLPH3 promoted VM in glioblastoma cells and that the corresponding mechanism was associated with the EMT. Our finding suggests that GOLPH3 may represent a promising therapeutic target for mitigating the recurrence and invasion of gliomas.

BMAL1 Suppresses Proliferation, Migration, and Invasion of U87MG Cells by Downregulating Cyclin B1, Phospho-AKT, and Metalloproteinase-9.

Several studies have shown that brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1), an important molecule for maintaining circadian rhythms, inhibits the growth and metastasis of tumor cells in several types of cancer, including lung, colon, and breast cancer. However, its role in glioblastoma has not yet been established. Here, we addressed the function of BMAL1 in U87MG glioblastoma cells with two approaches—loss and gain of function. In the loss of function experiments, cell proliferation in U87MG cells transfected with small interfering RNA (siRNA) targeting BMAL1 was increased by approximately 24% (small interfering (si)-NC 0.91 ± 0.00 vs. si-BMAL1 1.129 ± 0.08) via upregulation of cyclin B1. In addition, cell migration and invasion of BMAL1 siRNA-treated glioblastoma cells were elevated by approximately 20% (si-NC 51.00 ± 1.53 vs. si-BMAL161.33 ± 0.88) and 209% (si-NC 21.28 ± 1.37 vs. si-BMAL1 44.47 ± 3.48), respectively, through the accumulation of phosphorylated-AKT (p-AKT) and matrix metalloproteinase (MMP)-9. Gain of function experiments revealed that adenovirus-mediated ectopic expression of BMAL1 in U87MG cells resulted in a 19% (Adenovirus (Ad)-vector 0.94± 0.03 vs. Ad-BMAL1 0.76 ± 0.03) decrease in cell proliferation compared with the control via downregulation of cyclin B1 and increased early and late apoptosis due to changes in the levels of BCL2-associated X protein (BAX), B-cell lymphoma 2 (BCL-2), and cleaved caspase-3. Likewise, cell migration and invasion were attenuated by approximately 24% (Ad-vector 55.00 ± 0.00 vs. Ad-BMAL1 41.83 ± 2.90) and 49% (Ad-vector 70.01 ± 1.24 vs. Ad-BMAL1 35.55 ± 1.78), respectively, in BMAL1-overexpressing U87MG cells following downregulation of p-AKT and MMP-9. Taken together, our results suggest that BMAL1 acts as an anti-cancer gene by altering the proliferation, migration, and invasion of glioblastoma cells. Therefore, the BMAL1 gene could be a potential therapeutic target in the treatment of glioblastoma.

The Anti-Tumorigenic Activity of Sema3C in the Chick Embryo Chorioallantoic Membrane Model.

Sema3C protein, a member of the class 3 family of secreted semaphorins, play an important role in tumor development by regulating cell proliferation, migration, invasion, and angiogenesis processes. Depending on the type and malignancy grade of the tumor, Sema3C function remains controversial. In this study, we constructed a stably overexpressing Sema3C glioblastoma cell line U87 MG and tested it on the chicken embryo chorioallantoic membrane (CAM) model with the aim to reveal Sema3C protein function on angiogenesis process in ovo. Our experiments showed that Sema3C not only affects angiogenesis of CAM by inhibiting neovascularization but also acts as an anti-tumorigenic molecule by hampering U87 MG cell invasion into mesenchyme. The effects of Sema3C on CAM were similar to the effects of anti-epileptic drug sodium valproate (NaVP). Both, anti-angiogenic and anti-tumorigenic activities of Sema3C were enhanced by the treatment of NaVP and, importantly, were not attributed to the cytotoxic effects. Our studies suggest that Sema3C could be a promising target for glioblastoma treatment.

Targeted and effective glioblastoma therapy via aptamer-modified tetrahedral framework nucleic acid-paclitaxel nanoconjugates that can pass the blood brain barrier

Targeted DNA nanoparticles have been identified as one of the most promising nanocarriers in anti-glioma drug delivery. We established a multifunctional nanosystem for targeted glioma therapy. Tetrahedral framework nucleic acid (tFNA), entering U87MG cells and bEnd.3 cells, was chosen to deliver two aptamers, GMT8 and Gint4.T, and paclitaxel. GMT8 and Gint4.T, which specifically bind with U87MG cells and with PDGFRβ, were linked with tFNA, to form Gint4.T-tFNA-GMT8 (GTG). GTG was efficiently internalized by U87MG and bEnd.3 cells and penetrated an in-vitro blood–brain-barrier model. GTG loaded with paclitaxel (GPC) had potentiated anti-glioma efficacy. It inhibited the proliferation, migration, and invasion of U87MG cells, and enhanced apoptosis induction in these cells. The expression of apoptosis-related proteins was significantly changed after treatment with GPC, confirming apoptosis induction. Our study demonstrated that the combination of GTG and paclitaxel has great potential for glioma treatment and tFNA shows great promise for use in drug delivery.

Abstract 185: Direct cytotoxic effect of a novel anti-angiogenic drug F16 towards U87MG glioblastoma cell line

Abstract Glioblastoma multiforme (GBM) is one of the most aggressive and lethal types of brain cancers with low 5-year survival rate. Therefore, search for better drugs and effective treatment strategies for GBM to improve patient outcomes is continuing. Since GBM is one of the most highly vascularized solid tumors and its growth is angiogenesis-dependent, antagonizing tumor angiogenesis by using angiogenesis inhibitors seems to be one of the promising approaches. In this context, intensive pre-clinical evaluation of our patented anti-angiogenic compound, code-named F16, has exhibited potent anti-angiogenic and anti-tumor activities via selectively antagonizing VEGFR-2 in both in vitro and in vivo models. More importantly, assessment of biochemical parameters that are reflecting the safety of F16 in the in vivo system showed no alterations in the toxicological parameters of heart, liver, kidney, and pancreas, after 30 days of treatment, at the dose of 100 mg/kg body weight. Hence, we tested the direct effects of F16 for inhibiting the growth, angiogenesis and the migratory abilities of the U87MG glioblastoma cells, which are known to express high levels of VEGFR. Our in vitro studies have confirmed potent inhibitory effects of F16 towards the migration and invasion of U87MG cells, and also revealed potent cytotoxic effects (IC50 26 µM) against U87MG cells in comparison to Temozolomide (IC50 430 µM) treatment. In addition, F16 inhibited the phosphorylation of VEGFR-2 through competitive binding and also induced cell cycle arrest and apoptosis by activating p53 pathway in U87MG cells. Furthermore, our in vivo results with ectopically implanted xenograft model confirm the fact that F16 can significantly inhibit tumor growth in the mice implanted with U87MG glioblastoma cell line. Based on our preliminary results, we are proposing that F16 could be a potential candidate for treating GBM, either in monotherapy or in combination with a cytoreductive drug. (This research was supported by the generous funds provided by the Community Foundation of Broward, Florida and also by the Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida) Citation Format: Mohammad Algahtani, Khalid Alhazzani, Thiagarajan Venkatesan, Ali Alaseem, Sivanesan Dhandayuthapani, Appu Rathinavelu. Direct cytotoxic effect of a novel anti-angiogenic drug F16 towards U87MG glioblastoma cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 185.

Ubiquitin carboxyl-terminal hydrolase isozyme L5 inhibits human glioma cell migration and invasion via downregulating SNRPF.

Ubiquitin C-terminal Hydrolase-L5 (UCH-L5/UCH37), a member of the deubiquitinases (DUBs), suppresses protein degeneration via removing ubiquitin from the distal subunit of the polyubiquitin chain. The activity of UCH-L5 is enhanced when UCH-L5 combines with proteasome 19S regulatory subunit by Rpn13/Admr1 receptor and inhibited when UCH-L5 interacts with NFRKB. But the role of UCH-L5 in gliomas remains unknown. In this study, analysis of 19 frozen and 51 paraffin-embedded clinic pathological cases showed that UCH-L5 expression in glioma tissues was lower than normal brain tissues. In vitro, we found that UCH-L5 could inhibit migration and invasion of U87MG and U251 cells. It has been reported that the expression of SNRPN, SNRPF, and CKLF was abnormal in gliomas or other tumors. We also found that SNRPF-siRNA, SNRPN-siRNA and CKLF-siRNA could inhibit migration and invasion of U87MG cells. And knockdown of UCH-L5 expression improved both mRNA expression and protein level of SNRPF. The relationship between UCH-L5 and SNRPF was further confirmed in 293T cells. Our study showed that UCH-L5 could inhibit migration and invasion of glioma cells via down regulating expression of SNRPF. And the above findings suggest that UCH-L5 may inhibit occurrence and metastasis of gliomas.

PDIA6 regulation of ADAM17 shedding activity and EGFR-mediated migration and invasion of glioblastoma cells.

OBJECTIVE In patients with glioblastoma, local invasion of tumor cells causes recurrence and shortens survival. The goal of this study was to determine whether protein disulfide isomerase (PDI) A6 regulates migration and invasion of glioblastoma cells and the associated factors. METHODS U87MG cells were treated with either PDIA6 or ADAM17 small interfering RNA (siRNA) fragments or with both types of siRNA fragments, and expression was confirmed by reverse transcription-polymerase chain reaction and Western blot. Migration and invasion were assessed using a wound-healing assay, a Matrigel assay, and an organotypic culture system. After the U87MG cells were treated with siRNAs and epidermal growth factor receptor (EGFR) inhibitors, the expression of matrix metalloproteinase-2 (MMP-2), membrane Type 1-matrix metalloproteinase (MT1-MMP), integrin, phosphorylated focal adhesion kinase (pFAK), and phosphorylated EGFR (pEGFR) was detected by Western blotting and zymography. RESULTS U87MG cell migration and invasion increased significantly after inhibition of PDIA6. The MMP-2 activation ratio and ADAM17 activity (as a sheddase of the proligand) increased, and expression of pEGFR, pFAK, integrin α5β3, and MT1-MMP was induced, compared with control levels. Furthermore, heparin-binding epidermal growth factor (EGFR signaling ligand) was highly expressed in PDIA6-knockdown cells. After siPDIA6-transfected U87MG cells were treated with EGFR signaling inhibitors, expression of pFAK, MMP-2, and MT1-MMP decreased and invasion decreased significantly. Simultaneous double-knockdown of PDIA6 and ADAM17 reduced pEGFR and pFAK expression, compared with control levels. CONCLUSIONS The authors propose that inhibiting PDIA6 could transduce EGFR signaling by activating and inducing ADAM17 during migration and invasion of U87MG glioblastoma cells. The results of this study suggest that PDIA6 is an important component of EGFR-mediated migration and invasion of U87MG cells. This is the first report of the effects of PDIA6 on migration and invasion in glioblastoma.

Desmethylanhydroicaritin isolated from Sophora flavescens, shows antitumor activities in U87MG cells via inhibiting the proliferation, migration and invasion.

This study is the first report of the antitumor activities of desmethylanhydroicaritin (DMAI) isolated from Sophora flavescens on U87MG cells. Human glioblastoma is one of the most aggressive malignant type of brain tumors and highly diffuses to around normal brain tissues. DMAI showed anti-proliferation effects on U87MG cells at the concentration of 30μM, however did not affect to HEK-293 cells. DMAI induced anti-proliferation effects via ERK/MAPK, PI3K/Akt/mTOR signal pathway and G2/M phase cell cycle arrest. DMAI led to morphological change and inhibition of filapodia formation through regulation of Rac 1 and Cdc 42. In addition, migration and invasion of U87MG cells were inhibited by DMAI via down-regulation of matrix metalloproteinase (MMP) -2 and MMP -9 expressions and activities. Our results suggest that DMAI has a potential as a therapeutic agent against glioblastoma cells.

Abstract 2279: The oncogenic role of TRPM7 in cell proliferation and invasion of U87MG glioma cells

Abstract Background: We have previously reported that suppression of TRPM7 channels inhibit proliferation, migration, and invasion of malignant human glioma cells (CNS Neuroscience &amp; Therapeutics, in press) using A172 glioma cell line and brain tissue of human glioma. By studying glioma cancer stem cells derived from A172 cells, we further found that TRPM7 channels regulate glioma stem cell growth/proliferation through STAT3 and Notch signaling pathways (Cellular Signaling, 2014; 26: 2773-2781). However, the genetic difference of in vitro cell lines mirrors the diversity of individual patient cases. For instance, Ke et al reported that the differences in tumorigenicity among the different glioma cell lines were associated with the expression levels of bFGF and/or VEGF, two potent angiogenic factors in gliomas (Clin Cancer Res 2000; 6: 2562-2572). Interestingly, A172 cells produce a high-level bFGF, while U87MG cells secrete a significantly higher level of VEGF than other glioma cells. To determine whether our previous findings are not limited to A172 cells, we examined the role of TRPM7 channels in aforementioned malignant features of U87MG cells as well. We hypothesize that TRPM7 promotes proliferation and invasion in U87MG glioma cells. Methods: 1) We examined TRPM7-like current using patch-clamp technique in U87MG glioma cells. 2) We examined the TRPM7 mRNA and protein expression using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot respectively. 3) We determined the effects of TRPM7 on glioma cell proliferation and invasion using MTT assay and transwell invasion assay respectively by downregulating TRPM7 expression using siTRPM7 and inhibiting TRPM7 function using 2-APB, a non-specific pharmacological inhibitor. Results: 1) Electrophysiological recording showed a TRPM7-like current induced by Ca2+ and Mg2+ removal, which suggested that TRPM7 channels also exist in U87MG cells. 2) PCR and Western blot showed that U87MG cells express TRPM7 mRNA and protein. 3) Treatment of U87MG cells with siTRPM7 significantly reduced TRPM7 expression. 4) The cell proliferation and invasion were significantly reduced when treated with siTRPM7 and 2-APB which indicate that TRPM7 promotes growth and invasion of U87MG cells. 5) Inhibition of TRPM7 activity blocked calcium induced cell proliferation further indicating that TRPM7 activity is required for cell proliferation. Conclusion: TRPM7 promotes proliferation and invasion of U87MG glioma cells. TRPM7 may play a generalized role in glioma initiation and progression and might be an important drug target of glioma. (This work is supported by R01NS066027, NIMHD S21MD000101, U54NS08932, and AHA 0840132.) Citation Format: Mingli Liu. The oncogenic role of TRPM7 in cell proliferation and invasion of U87MG glioma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2279. doi:10.1158/1538-7445.AM2015-2279

MiR-29s inhibit the malignant behavior of U87MG glioblastoma cell line by targeting DNMT3A and 3B

miR-29s (including miR-29a–c) have been confirmed to be effective tumor suppressors for a variety of malignant tumors including glioblastoma. Promoter hypermethylation resulting from DNMT3A and 3B overexpression is an important epigenetic mechanism for tumor suppressive gene silencing. Bioinformatics predicts both DNMT3A and 3B are targets of miR-29s, but the anti-glioblastoma effects of miR-29s induced DNMT3A/3B downregulation deserve further investigation. We herein demonstrated that miR-29s effectively blocked DNMT3A and 3B expression by degrading their mRNAs in U87MG glioblastoma cell line. Exogenous miR-29s substantially inhibited the proliferation, migration and invasion of U87MG cells, and promoted their apoptosis. These effects could be perfectly mimicked by a small interfering RNA against DNMT3A and 3B, and partially compromised by DNMT3A/3B expression plasmids co-transfection, suggesting that miR-29s exerted the above tumor suppressive effects at least partly by silencing DNMT3A/3B. These findings provide a rationale for miR-29s based therapeutic strategies against glioblastoma.

Design, synthesis, and evaluation of novel imidazo[1,2-a][1,3,5]triazines and their derivatives as focal adhesion kinase inhibitors with antitumor activity.

A series of triazinic inhibitors of focal adhesion kinase (FAK) have been recently shown to exert antiangiogenic activity against HUVEC cells and anticancer efficacy against several cancer cell lines. We report herein that we further explored the heterocyclic core of these inhibitors by a fused imidazole ring with the triazine to provide imidazo[1,2-a][1,3,5]triazines. Importantly, these new compounds displayed 10(-7)-10(-8) M IC50 values, and the best inhibitor showed IC50 value of 50 nM against FAK enzymatic activity. Several inhibitors potently inhibited the proliferation of a panel of cancer cell lines expressing high levels of FAK. Apoptosis analysis in U87-MG and HCT-116 cell lines suggested that these compounds delayed cell cycle progression by arresting cells in the G2/M phase of the cell cycle, retarding cell growth. Further investigation demonstrated that these compounds strongly inhibited cell-matrix adhesion, migration, and invasion of U87-MG cells.

Tristetraprolin inhibits the growth of human glioma cells through downregulation of urokinase plasminogen activator/urokinase plasminogen activator receptor mRNAs.

Urokinase plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR) play a major role in the infiltrative growth of glioblastoma. Downregulatoion of the uPA and uPAR has been reported to inhibit the growth glioblastoma. Here, we demonstrate that tristetraprolin (TTP) inhibits the growth of U87MG human glioma cells through downregulation of uPA and uPAR. Our results show that expression level of TTP is inversely correlated with those of uPA and uPAR in human glioma cells and tissues. TTP binds to the AU-rich elements within the 3' untranslated regions of uPA and uPAR and overexpression of TTP decreased the expression of uPA and uPAR through enhancing the degradation of their mRNAs. In addition, overexpression of TTP inhibited the growth and invasion of U87MG cells. Our findings implicate that TTP can be used as a promising therapeutic target to treat human glioma.

Protein kinase D2 regulates migration and invasion of U87MG glioblastoma cells in vitro

Glioblastoma multiforme (GBM) is the most common malignant brain tumor, which, despite combined modality treatment, reoccurs and is invariably fatal for affected patients. Recently, a member of the serine/threonine protein kinase D (PRKD) family, PRKD2, was shown to be a potent mediator of glioblastoma growth. Here we studied the role of PRKD2 in U87MG glioblastoma cell migration and invasion in response to sphingosine-1-phosphate (S1P), an activator of PRKD2 and a GBM mitogen. Time-lapse microscopy demonstrated that random cell migration was significantly diminished in response to PRKD2 silencing. The pharmacological PRKD family inhibitor CRT0066101 decreased chemotactic migration and invasion across uncoated or matrigel-coated Transwell inserts. Silencing of PRKD2 attenuated migration and invasion of U87MG cells even more effectively. In terms of downstream signaling, CRT0066101 prevented PRKD2 autophosphorylation and inhibited p44/42 MAPK and to a smaller extent p54/46 JNK and p38 MAPK activation. PRKD2 silencing impaired activation of p44/42 MAPK and p54/46 JNK, downregulated nuclear c-Jun protein levels and decreased c-JunS73 phosphorylation without affecting the NFκB pathway. Finally, qPCR array analyses revealed that silencing of PRKD2 downregulates mRNA levels of integrin alpha-2 and -4 (ITGA2 and -4), plasminogen activator urokinase (PLAU), plasminogen activator urokinase receptor (PLAUR), and matrix metallopeptidase 1 (MMP1). Findings of the present study identify PRKD2 as a potential target to interfere with glioblastoma cell migration and invasion, two major determinants contributing to recurrence of glioblastoma after multimodality treatment.

Role of 14-3-3-beta in the migration and invasion in human malignant glioma cell line U87MG

Purpose: To assess the influence of 14-3-3-beta in modulating the migration and invasion of human glioma cells.Methods: To profile the genes associated with malignant glioma cell motility, differential display-polymerase chain reaction was performed and the findings were validated by Northern blotting in the U343MG-A, U87MG, and U87MG-10' human glioma cell lines. Antisense 14-3-3-beta cDNA plasmid was transfected into U87MG (‘U87-YA-3’). To follow motility changes after transfection, simple scratch test and matrigel assay were performed. Morphological and cytoskeletal changes were documented by light and confocal microscopy. In addition, doubling times of the transfectant and endogenous 14-3-3-beta levels were determined in various glioma cell lines with different motilities.Results: 14-3-3-beta was highly expressed in U87MG cells. U87-YA-3 cells became small and flat, and actin was depolarized. Furthermore, U87-YA-3 cell motility was inhibited markedly versus parental U87MG cells. The doubling times of transfected and parent cells were 32 and 37 hours, respectively. Endogenous 14-3-3-beta expression in the human glioma cell lines was proportional to their migratory and invasive abilities.Conclusion: 14-3-3-beta modulates the migration and invasion in U87MG cells, which may be useful in developing therapeutic approaches for the treatment of glioma.

Dexamethasone reduced invasiveness of human malignant glioblastoma cells through a MAPK phosphatase-1 (MKP-1) dependent mechanism

Dexamethasone has been shown to inhibit tumor invasiveness. In the present study, the effects of dexamethasone on matrix metalloproteinases-2 (MMP-2) secretion, cell invasiveness, and intravasation in human U87MG glioma cells were examined. Dexamethasone decreased MMP-2 secretion and cell invasiveness in human glioma cells. Incubation of cells with dexamethasone increased mitogen activated protein kinase phosphatase-1 (MKP-1) expression. Ectopic expression of MKP-1 decreased cell invasiveness in vitro and intravasation in vivo. Because expression of inducible nitric oxide synthase (iNOS) has been implicated in the progression of malignant gliomas, we next investigated the possible roles of NO − in MMP-2 secretion and cell invasiveness in human U87MG glioma cells. Treatment of glioma cells with nitric oxide donor, sodium nitroprusside (SNP), increased MMP-2 secretion and the capacity of cell invasion in U87MG cells. Addition of dexamethasone or ectopic expression of wild-type MKP-1 suppressed the SNP-stimulated MMP-2 activation and glioma cell invasiveness in U87MG cells. Taken together, these results suggest that dexamethasone may suppress MMP-2 secretion and cell invasion through MKP-1 induction in human glioma cells.