Temozolomide-induced inhibition of pituitary adenoma cells

2011 ◽  
Vol 114 (2) ◽  
pp. 354-358 ◽  
Author(s):  
Jason Sheehan ◽  
Jessica Rainey ◽  
James Nguyen ◽  
Ruthie Grimsdale ◽  
Shaojie Han
Keyword(s):  
Cell Proliferation ◽  
Pituitary Adenoma ◽  
Cell Lines ◽  
Pituitary Adenomas ◽  
Apoptotic Cell ◽  
Multimodality Treatment ◽  
Prolactin Secretion ◽  
Significant Inhibition ◽  
Gh3 Cells ◽  
Tunel Staining

Object Aggressive pituitary adenomas frequently require multimodality treatment including pituitary-suppressive medications, microsurgery, and radiation therapy or radiosurgery. The effectiveness of temozolomide in terms of growth suppression and decreased hormonal production is evaluated. Methods Three pituitary adenoma cell lines—MMQ, GH3, and AtT20—were used. A dose escalation of temozolomide was performed for each cell line, and inhibition of cell proliferation was assessed using an MTT assay. Concentrations of temozolomide that produced statistically significant inhibition of cell proliferation for each cell type were identified. Extent of apoptosis for each selected temozolomide concentration was studied using TUNEL staining. The effect of temozolomide on prolactin secretion in MMQ and GH3 cells was also measured via ELISA. Results Significant inhibition of cell proliferation was noted for MMQ and GH3 cells at a concentration of 250 μM temozolomide. The AtT20 cells demonstrated statistically significant cell inhibition at a concentration of only 50 μM temozolomide (p < 0.05). Apoptosis significantly increased in all cell lines in as little as 24 hours of incubation at the respective temozolomide concentrations (p < 0.05). Prolactin secretion in the prolactin secreting MMQ and GH3 cell lines was inhibited by 250 μM temozolomide. Conclusions Temozolomide inhibits cell proliferation and induces apoptotic cell death in aggressive pituitary adenoma cells. A reduction in hormonal secretion in prolactinoma cells was also afforded by temozolomide. Temozolomide may prove useful in the multimodality management of aggressive pituitary adenomas.

scholarly journals HIF-1α Inhibition Sensitized Pituitary Adenoma Cells to Temozolomide by Regulating Presenilin 1 Expression and Autophagy

2016 ◽  
Vol 15 (6) ◽  
pp. NP95-NP104 ◽  
Author(s):  
Zhang kun ◽  
Yang yuling ◽  
Wang dongchun ◽  
Xie bingbing ◽  
Li xiaoli ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Pituitary Adenomas ◽  
Ph Value ◽  
Hypoxia Inducible Factor ◽  
Presenilin 1 ◽  
Gh3 Cells ◽  
Lysosomal Ph ◽  
Hypoxia Inducible Factor 1Α ◽  
Anticancer Effects ◽  
Autophagy Induction

Pituitary adenomas usually develop temozolomide resistance, which could compromise the anticancer effects of temozolomide. Suppression of hypoxia-inducible factor 1α has been shown to sensitize glioblastoma cells to temozolomide treatment according to previous reports. However, whether and how the suppression of hypoxia-inducible factor 1α could sensitize pituitary adenomas to temozolomide treatment are still poorly understood. In the present study, using hypoxia-inducible factor 1α knockdown strategy, we demonstrated for the first time that hypoxia-inducible factor 1α knockdown could inhibit temozolomide-induced autophagy in rat pituitary adenoma GH3 cells and thus increase antitumor efficacy of temozolomide. Furthermore, we found hypoxia-inducible factor 1α knockdown could block autophagy process through neutralizing lysosomal pH value but not inhibiting autophagy induction. Finally, we found hypoxia-inducible factor 1α could regulate lysosomal pH value through regulating full length presenilin 1 expression, and exogenous reexpression of presenilin 1could restore lysosome acidic levels. Our data indicated hypoxia-inducible factor 1α knockdown could be a potential approach to improve the efficacy of temozolomide therapy for pituitary adenomas.

scholarly journals Mammalian target of rapamycin inhibitors rapamycin and RAD001 (everolimus) induce anti-proliferative effects in GH-secreting pituitary tumor cells in vitro

2009 ◽  
Vol 16 (3) ◽  
pp. 1017-1027 ◽  
Author(s):  
Alexander Gorshtein ◽  
Hadara Rubinfeld ◽  
Efrat Kendler ◽  
Marily Theodoropoulou ◽  
Vesna Cerovac ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cyclin D1 ◽  
Pituitary Adenomas ◽  
Pituitary Tumor ◽  
Mammalian Target Of Rapamycin ◽  
Pituitary Tumors ◽  
Mtor Inhibitors ◽  
Target Of Rapamycin ◽  
Gh3 Cells ◽  
Mtor Inhibition

The effect of mammalian target of rapamycin (mTOR) inhibitors on pituitary tumors is unknown. Akt overexpression was demonstrated in pituitary adenomas, which may render them sensitive to the anti-proliferative effects of these drugs. The objective of the study was to evaluate the anti-proliferative efficacy of the mTOR inhibitor, rapamycin, and its orally bioavailable analog RAD001 on the GH-secreting pituitary tumor GH3 and MtT/S cells and in human GH-secreting pituitary adenomas (GH-omas) in primary cell cultures. Treatment with rapamycin or RAD001 significantly decreased the number of viable cells and cell proliferation in a dose- and time-dependent manner. This was reflected by decreased phosphorylation levels of the downstream mTOR target p70S6K. Rapamycin treatment of GH3 cells induced G0/G1 cell cycle arrest. In other tumor cell types, this was attributed to a decrease in cyclin D1 levels. However, rapamycin did not affect cyclin D1 protein levels in GH3 cells. By contrast, it decreased cyclin D3 and p21/CIP, which stabilizes cyclin D/cyclin-dependent kinase 4 (cdk4) complexes. Rapamycin inhibited FCS-induced retinoblastoma phosphorylation and subsequent E2F-transcriptional activity. In response to decreased E2F activity, the expression of the E2F-regulated genes cyclin E and cdk2 was reduced. Our results showed that mTOR inhibitors potently inhibit pituitary cell proliferation, suggesting that mTOR inhibition may be a promising anti-proliferative therapy for pituitary adenomas. This therapeutic manipulation may have beneficial effects particularly for patients harboring invasive pituitary tumors resistant to current treatments.

scholarly journals Localization of vascular endothelial growth factor (VEGF) receptors in normal and adenomatous pituitaries: detection of a non-endothelial function of VEGF in pituitary tumours

2006 ◽  
Vol 191 (1) ◽  
pp. 249-261 ◽  
Author(s):  
Chiara Onofri ◽  
Marily Theodoropoulou ◽  
Marco Losa ◽  
Eberhard Uhl ◽  
Manfred Lange ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Cell Proliferation ◽  
Endothelial Cells ◽  
Pituitary Adenoma ◽  
Growth Factor ◽  
Pituitary Adenomas ◽  
Vascular Endothelial ◽  
Vegf Receptors ◽  
Pituitary Tumours ◽  
Endothelial Growth Factor

As for any solid tumour, pituitary adenoma expansion is dependent on neovascularization through angiogenesis. In this process, vascular endothelial growth factor (VEGF) and its receptors VEGFR-1, VEGFR-2 and neuropilin-1 (NRP-1) may play an outstanding role. The intention of this work was to study the expression/localization and possible function of VEGF receptors in pituitary adenomas. VEGF receptor mRNA and protein expression was studied by in situ hybridization, immunohistochemistry and RT-PCR in 6 normal human pituitaries, 39 human pituitary adenomas and 4 rodent pituitary adenoma cell lines. VEGFR-1 expressing somatotroph MtT-S cells were used as a model to study the role of VEGF on cell proliferation and to elucidate the underlying mechanism of action. In normal pituitaries, VEGFR-1 was detected in endocrine cells, whereas VEGFR-2 and NRP-1 were exclusively expressed in endothelial cells. In pituitary tumours, a heterogeneous VEGFR expression pattern was observed by IHC. VEGFR-1, VEGFR-2 and NRP-1 were detected in 24, 18 and 17 adenomas respectively. In the adenomas, VEGFR-1 was expressed in epithelial tumour cells and VEGFR-2/NRP-1 in vessel endothelial cells. Functional studies in VEGFR-1-positive MtT-S cells showed that the ligands of VEGFR-1 significantly stimulated cell proliferation. This effect was mediated through the phosphatidylinositol-3-kinase-signalling pathway and involves induction of cyclin D1 and Bcl-2. Based on our results, we speculate that the ligands of VEGF receptors, such as VEGF-A and placenta growth factor, not only play a role in angiogenesis in pituitary adenomas, but also affect the growth of pituitary tumour cells through VEGFR-1.

scholarly journals Curcumin Sensitizes Prolactinoma to Bromocriptine by Activating the ERK/EGR1 and Inhibiting AKT/GSK3β Signaling Pathway

2021 ◽  
Author(s):  
Chao Tang ◽  
Junhao Zhu ◽  
Feng Yuan ◽  
Jin Yang ◽  
Xiangming Cai ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Expression Profiles ◽  
Inhibitory Effect ◽  
Gh3 Cells ◽  
Growth Inhibitory Effect ◽  
Growth Inhibitory ◽  
The Difference

Abstract Although bromocriptine (BRC) as first-line drugs are recommended for treating patients with prolactinoma, a minority of patients with prolactinoma resistance to BRC. Moreover, our previous study showed that the difference in drug sensitivity in BRC- treated rat prolactinoma cells, MMQ cells are more resistant to BRC, and GH3 cells are more sensitive to BRC. Curcumin (Cur) has been shown to inhibit proliferation of prolactinoma cell lines. The aim of this study is to further investigate whether Cur could enhance the growth-inhibitory effect of BRC resistance on prolactinoma cell lines and its possible mechanism. CCK-8 kit was used to test cell growth. Cell-cycle analysis and apoptosis was performed by flow cytometry. Electron microscopy was used to test autophagosome. The mRNA expression profiles were analysed using the Affymetrix Gene-Chip array. Western blotting was used to test protein expression. Our data showed that Cur enhanced the growth-inhibitory effect of BRC on GH3 and MMQ cell proliferation. BRC and Cur both induced cell apoptosis, and Cur could significantly increase the apoptosis of BRC on pituitary adenoma cells through the ERK/EGR1 signaling pathway. Moreover, Cur could enhance the autophagic cell death (ACD) of BRC on tumor cell by inhibiting the AKT/GSK3β signaling pathway. The same results were confirmed in vivo study. Taken together, Cur sensitizes rat pituitary adenoma cell to BRC by activating the ERK/EGR1 and inhibiting AKT/GSK3β signaling pathway.

The MDM2 Antagonist Nutlin-3 Is Lethal to Mantle Cell Lymphoma with Wild Type p53.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1382-1382
Author(s):  
Yoko Tabe ◽  
Denise Sebasigari ◽  
Martina Rudelius ◽  
Stefania Pittaluga ◽  
Mark Raffel
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Target Genes ◽  
Cell Lymphoma ◽  
Apoptotic Cell ◽  
P53 Mutation ◽  
Mantle Cell ◽  
P53 Target Genes

Abstract Mantle cell lymphoma (MCL) has one of the poorest overall prognoses of the non-Hodgkin lymphomas, and is resistant to standard chemotherapy. P53 mutations are rare in typical mantle cell lymphoma and occur in only about 1/3 of the less common blastoid variant. The relatively low overall rate of p53 mutation in MCL suggests that this lymphoma may be a good candidate for biologic therapies that upregulate p53 and lead to cell death. Nutlin-3 is a novel small-molecule antagonist of MDM2 that efficiently activates p53 by blocking the MDM2-p53 interaction. In this study, we investigated the effects of nutlin-3 in 5 MCL cell lines with known p53 mutation status (wt-p53: REC-1, Z138, Granta-519, JVM-2; mt-p53: Jeko-1). IC50s for all cell lines were determined, and the activation of p53 and multiple p53 target genes were studied by western blot analysis. Cell proliferation and apoptosis were assessed using the MTT test and flow cytometry. Treatment with Nutlin-3 resulted in a marked reduction in cell proliferation/viability, and an increase in the apoptotic fraction, in a time and concentration-dependent manner in wt-p53 cells (IC50 at 48 hrs; 7.5 uM for Granta-519, 9.2 uM for REC-1, 0.5 uM for Z138, and 5.7 uM for JVM-2), while mt-p53 Jeko was resistant to nutlin-3 treatment (IC50>60 uM), and showed no increase in the apoptotic cell fraction. In the wt-p53 MCL cell lines, nutlin-3 treatment increased the cellular levels of p53, and several p53 dependent proteins including p21, MDM2 itself and the proapoptotic BH3-only protein Puma, while there was no change in the levels of these proteins in Jeko-1. Recently, attention has been focused on novel p53 target genes that function to inhibit cell growth and proliferation, rather than by inducing apoptosis. These include the AKT-mTOR regulators PTEN, TSC2 and AMPKβ1. We saw no increase in these novel p53 targets in any of the cell lines analyzed, suggesting that nutlin-3-activated p53 activates only a subset of its possible targets. These findings demonstrate that nutlin-3 successfully activates wt-p53 in mantle cell lymphoma leading to the upregulation of traditional targets such as p21 and proapoptotic proteins including Puma, and result in apoptotic cell death. The data suggest that p53 activators such as nutlin-3 may be effective agents in the treatment of mantle cell lymphoma.

Effect of GnRH-associated peptide on prolactin secretion from human lactotrope adenoma cells in culture

1987 ◽  
Vol 116 (1) ◽  
pp. 81-84 ◽  
Author(s):  
Miyuki Ishibashi ◽  
Tohru Yamaji ◽  
Fumimaro Takaku ◽  
Akira Teramoto ◽  
Takanori Fukushima ◽  
...  
Keyword(s):  
Pituitary Adenomas ◽  
Inhibitory Effect ◽  
Prolactin Secretion ◽  
Significant Inhibition ◽  
The Other ◽  
Human Pituitary ◽  
Gh Secretion ◽  
Cells In Culture ◽  
Other Hand ◽  
Transsphenoidal Adenomectomy

Abstract. The effect of GnRH-associated peptide on PRL secretion by human pituitary lactotropes in culture was studied. Pituitary adenomas obtained at selective transsphenoidal adenomectomy from a patient with prolactinoma, and two patients with mixed GH- and PRL-secreting pituitary adenomas were cultured in monolayer. When cells were incubated with dopamine (10 nmol/l), a significant inhibition in PRL secretion was observed in all the experiments, which was blocked by co-incubation with haloperidol. In mixed GH- and PRL-secreting adenoma cells, dopamine likewise decreased GH secretion. Incubation of cells with synthetic GnRH-associated peptide at concentrations up to 100 nmol/l, on the other hand, failed to affect both PRL and GH secretion. These results suggest that synthetic GnRH-associated peptide has no inhibitory effect on PRL secretion in human pituitary lactotropes.

scholarly journals Melatonin decreases cell proliferation, impairs myogenic differentiation and triggers apoptotic cell death in rhabdomyosarcoma cell lines

2015 ◽  
Vol 34 (1) ◽  
pp. 279-287 ◽  
Author(s):  
SILVIA CODENOTTI ◽  
MICHELA BATTISTELLI ◽  
SABRINA BURATTINI ◽  
SARA SALUCCI ◽  
ELISABETTA FALCIERI ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Myogenic Differentiation ◽  
Apoptotic Cell Death ◽  
Rhabdomyosarcoma Cell

MiR-3144 Suppresses Cell Proliferation, Migration, Invasion and Promotes Cell Apoptosis by Targeting Steap4 in Hepatocellular Carcinoma

2019 ◽  
Vol 9 (8) ◽  
pp. 1100-1107
Author(s):  
Qiuyuan Shi ◽  
Dandan Shen ◽  
Yuanjiang Shang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Cell Apoptosis ◽  
Apoptotic Cell ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Invasion And Migration ◽  
Novel Target ◽  
Hcc Cells

Background: MicroRNAs (miRNAs) play important roles in the carcinogenesis and progression of hepatocellular carcinoma (HCC). Previous studies have shown that miR-3144 is down-regulated in HCC tissues. The present study investigated the expression and biological roles, underlying mechanisms of miR-3144 in HCC cell lines. Methods and material: RT-qPCR analysis was performed to detect miR-3144 expression in the HCC cell lines and normal hepatic cell line. CCK-8 assay showed that the effect of miR-3144 expression on cell proliferation. Using wound healing assay and Transwell assay to detect the effect of miR-3144 on cell invasion and migration of HCC. Flow cytometry assay showed that miR-3144 induced apoptotic cell death in the SK-HEP-1 cells. Luciferase reporter assay was performed to evaluate the interaction between miR-3144 and the Steap4 3′-UTR. Western blotting assay were performed to investigate the effect of miR-3144 expression on the expression of CDK2, cyclinE1, p21, MMP2, MMP9 and Steap4. Results: MiR-3144 expression was downregulated in HCC cell lines. MiR-3144 overexpression inhibited the proliferation of HCC cells via regulating CDK2, cyclinE1 and p21 in SK-HEP-1 cells. MiR-3144 suppressed the migration and invasion of HCC cells via decreasing the MMP2 and MMP9. Further, miR-3144 promotes cell apoptosis of HCC. Moreover, miR-3144 negatively regulated Steap4 expression by directly binding to the 3′-UTR of Steap4 mRNA. Conclusion: Our results suggested that miR-3144 may be a novel target for future HCC therapy.

scholarly journals A Bispecific Inhibitor of the EGFR/ADAM17 Axis Decreases Cell Proliferation and Migration of EGFR-Dependent Cancer Cells

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 411
Author(s):  
Abel Soto-Gamez ◽  
Deng Chen ◽  
Anke G.E. Nabuurs ◽  
Wim J Quax ◽  
Marco Demaria ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Fusion Protein ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Mutant Cell ◽  
Growth Factor Receptor ◽  
Autocrine Signaling ◽  
Inhibition Of Proliferation ◽  
Innovative Strategy ◽  
Egfr Ligands

Dysregulated epidermal growth factor receptor (EGFR) is an oncogenic driver of many human cancers, promoting aberrant cell proliferation, migration, and survival. Pharmacological targeting of EGFR is often challenged by acquired mechanisms of resistance. Ligand-dependent mechanisms in EGFR wild-type cells rely on ligand or receptor overexpression, allowing cells to outcompete inhibitors and perpetuate signaling in an autocrine manner. Importantly, EGFR ligands are synthesized as membrane-bound precursors that must be solubilized to enable receptor-ligand interactions. The A disintegrin and metalloproteinase 17 (ADAM17) is considered the main sheddase of several EGFR ligands, and a potential pharmacological target. However, its broad substrate range and ubiquitous expression complicate its therapeutic targeting. Here, we present a novel bispecific fusion protein construct consisting of the inhibitory prodomain of ADAM17 (TPD), fused to an EGFR-targeting designed ankyrin repeat protein (DARPin). TPD is a natural inhibitor of ADAM17, maintaining the protease in a zymogen-like form. Meanwhile, the high affinity anti-EGFR DARPin E01 binds to EGFR and inhibits ligand binding. The resulting fusion protein E01-GS-TPD retained binding ability to both molecular targets EGFR and ADAM17. The large difference in affinity for each target resulted in enrichment of the fusion protein in EGFR-positive cells compared to EGFR-negative cells, suggesting a possible application in autocrine signaling inhibition. Accordingly, E01-GS-TPD decreased migration and proliferation of EGFR-dependent cell lines with no significant increase in apoptotic cell death. Finally, inhibition of proliferation was observed through EGFR ligand-dependent mechanisms as growth inhibition was not observed in EGFR mutant or KRAS mutant cell lines. The use of bispecific proteins targeting the EGFR/ADAM17 axis could be an innovative strategy for the treatment of EGFR-dependent cancers.

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