scholarly journals Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Stuart R. Pierce ◽  
Ziwei Fang ◽  
Yajie Yin ◽  
Lindsay West ◽  
Majdouline Asher ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Endometrial Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Dopamine Receptor ◽  
Therapeutic Strategy ◽  
Diet Induced Obesity ◽  
Endometrioid Endometrial Cancer

Abstract Background ONC201 is a dopamine receptor D2 (DRD2) antagonist that inhibits tumor growth in preclinical models through ClpP activation to induce integrated stress response pathway and mitochondrial events related to inhibition of cell growth, which is being explored in clinical trials for solid tumors and hematological malignancies. In this study, we investigated the anti-tumorigenic effect of ONC201 in endometrial cancer cell lines and a genetically engineered mouse model of endometrial cancer. Methods Cell proliferation was assessed by MTT and colony formation assays. Cell cycle and apoptosis were evaluated by Cellometer. Invasion capacity was tested using adhesion, transwell and wound healing assays. LKB1fl/flp53fl/fl mouse model of endometrial cancer were fed a control low fat diet versus a high fat diet to mimic diet-induced obesity. Following tumor onset, mice were treated with placebo or ONC201. Metabolomics and lipidomics were used to identify the obesity-dependent effects of ONC201 in the mouse endometrial tumors. DRD2 expression was analyzed by immunohistochemistry in human endometrioid and serous carcinoma specimens. DRD2 mRNA expression from the Cancer Genome Atlas (TCGA) database was compared between the four molecular subtypes of endometrial cancer. Results Increasing DRD2 expression in endometrial cancer was significantly associated with grade, serous histology and stage, as well as worse progression free survival and overall survival. Higher expression of DRD2 mRNA was found for the Copy Number High (CNH) subtype when compared to the other subtypes. ONC201 inhibited cell proliferation, induced cell cycle G1 arrest, caused cellular stress and apoptosis and reduced invasion in endometrial cancer cells. Diet-induced obesity promoted endometrial tumor growth while ONC201 exhibited anti-tumorigenic efficacy in the obese and lean LKB1fl/fl/p53fl/fl mice. Metabolomic analysis demonstrated that ONC201 reversed the obesity-driven upregulation of lipid biosynthesis and reduced protein biosynthesis in obese and lean mice. Conclusion ONC201 has anti-tumorigenic effects in endometrial cancer cells and a transgenic mouse model of endometrial cancer, and DRD2 expression was documented in both human serous and endometrioid endometrial cancer. These studies support DRD2 antagonism via ONC201 as a promising therapeutic strategy for endometrial cancer that has already demonstrated pharmacodynamic activity and clinical benefit in both serous and endometrioid endometrial cancer patients.

scholarly journals Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer

2020 ◽  
Author(s):  
Stuart R. Pierce ◽  
Ziwei Fang ◽  
Yajie Yin ◽  
Lindsay West ◽  
Majdouline Asher ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Endometrial Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Dopamine Receptor ◽  
Therapeutic Strategy ◽  
Diet Induced Obesity ◽  
Dopamine Receptor D2 ◽  
Endometrioid Endometrial Cancer

Abstract BackgroundONC201 is a dopamine receptor D2 (DRD2) antagonist that inhibits tumor growth in preclinical models through ClpP activation to induce integrated stress response pathway and mitochondrial events related to inhibition of cell growth, which is being explored in clinical trials for solid tumors and hematological malignancies. In this study, we investigated the anti-tumorigenic effect of ONC201 in endometrial cancer cell lines and a genetically engineered mouse model of endometrial cancer.MethodsCell proliferation was assessed by MTT and colony formation assays. Cell cycle and apoptosis were evaluated by Cellometer. Invasion capacity was tested using adhesion, transwell and wound healing assays. LKB1fl/flp53fl/fl mouse model of endometrial cancer were fed a control low fat diet versus a high fat diet to mimic diet-induced obesity. Following tumor onset, mice were treated with placebo or ONC201. Metabolomics and lipidomics were used to identify the obesity-dependent effects of ONC201 in the mouse endometrial tumors. DRD2 expression was analyzed by immunohistochemistry in human endometriod and serous EC specimens. DRD2 mRNA expression from the Cancer Genome Atlas (TCGA) database was compared between the four molecular subtypes of endometrial cancer. ResultsIncreasing DRD2 expression in endometrial cancer was significantly associated with grade, serous histology and stage, as well as worse progression free survival and overall survival. Higher expression of DRD2 mRNA was found for the Copy Number High (CNH) subtype when compared to the other subtypes.. ONC201 inhibited cell proliferation, induced cell cycle G1 arrest, caused cellular stress and apoptosis and reduced invasion in endometrial cancer cells. Diet-induced obesity promoted endometrial tumor growth while ONC201 exhibited anti-tumorigenic efficacy in the obese and lean LKB1fl/fl/p53fl/fl mice. Metabolomic analysis demonstrated that ONC201 reversed the obesity-driven upregulation of lipid biosynthesis and reduced protein biosynthesis in obese and lean mice. ConclusionONC201 has anti-proliferative and anti-tumorigenic effects in endometrial cancer cells and mouse model, and DRD2 expression was documented in both human serous and endometrioid endometrial cancer. These studies support DRD2 antagonism via ONC201 as a promising therapeutic strategy for endometrial cancer that has already demonstrated pharmacodynamic activity and clinical benefit in both serous and endometrioid endometrial cancer patients.

scholarly journals The Effects of NT-1044, a Novel AMPK Activator, on Endometrial Cancer Cell Proliferation, Apoptosis, Cell Stress and In Vivo Tumor Growth

2021 ◽  
Vol 11 ◽  
Author(s):  
Dario R. Roque ◽  
Lu Zhang ◽  
Weiya Z. Wysham ◽  
Jianjun Han ◽  
Wenchuan Sun ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Endometrial Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Cell Lines ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Dose Dependent

ObjectivesAnti-diabetic biguanide drugs such as metformin may have anti-tumorigenic effects by behaving as AMPK activators and mTOR inhibitors. Metformin requires organic cation transporters (OCTs) for entry into cells, and NT-1044 is an AMPK activator designed to have greater affinity for two of these transporters, OCT1 and OCT3. We sought to compare the effects of NT-1044 on cell proliferation in human endometrial cancer (EC) cell lines and on tumor growth in an endometrioid EC mouse model.MethodsCell proliferation was assessed in two EC cell lines, ECC-1 and Ishikawa, by MTT assay after exposure to NT-1044 for 72 hours of treatment. Apoptosis was analyzed by Annexin V-FITC and cleaved caspase 3 assays. Cell cycle progression was evaluated by Cellometer. Reactive oxygen species (ROS) were measured using DCFH-DA and JC-1 assays. For the in vivo studies, we utilized the LKB1fl/flp53fl/fl mouse model of endometrioid endometrial cancer. The mice were treated with placebo or NT-1044 or metformin following tumor onset for 4 weeks.ResultsNT-1044 and metformin significantly inhibited cell proliferation in a dose-dependent manner in both EC cell lines after 72 hours of exposure (IC50 218 μM for Ishikawa; 87 μM for ECC-1 cells). Treatment with NT-1044 resulted in G1 cell cycle arrest, induced apoptosis and increased ROS production in both cell lines. NT-1044 increased phosphorylation of AMPK and decreased phosphorylation of S6, a key downstream target of the mTOR pathway. Expression of the cell cycle proteins CDK4, CDK6 and cyclin D1 decreased in a dose-dependent fashion while cellular stress protein expression was induced in both cell lines. As compared to placebo, NT-1044 and metformin inhibited endometrial tumor growth in obese and lean LKB1fl/flp53fl/fl mice.ConclusionsNT-1044 suppressed EC cell growth through G1 cell cycle arrest, induction of apoptosis and cellular stress, activation of AMPK and inhibition of the mTOR pathway. In addition, NT-1044 inhibited EC tumor growth in vivo under obese and lean conditions. More work is needed to determine if this novel biguanide will be beneficial in the treatment of women with EC, a disease strongly impacted by obesity and diabetes.

Lentivirus-Mediated RNA Interference Targeting the Long Noncoding RNA HOTAIR Inhibits Proliferation and Invasion of Endometrial Carcinoma Cells In Vitro and In Vivo

2014 ◽  
Vol 24 (4) ◽  
pp. 635-642 ◽  
Author(s):  
Jiaming Huang ◽  
Peiqi Ke ◽  
Luyan Guo ◽  
Wei Wang ◽  
Hao Tan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Endometrial Cancer ◽  
Endometrial Carcinoma ◽  
Cancer Cells ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Proliferation And Invasion

ObjectiveThe overexpression of long noncoding RNA HOTAIR is associated with various aggressive solid carcinomas. However, its relationship with endometrial carcinoma has not been reported. The present study aimed to investigate the expression of the long noncoding RNA HOTAIR in endometrial carcinoma, its relationship with the carcinoma’s clinicopathologic features, and the biological function of HOTAIR in regulating endometrial cancer cell proliferation and invasion in vitro and in vivo.MethodsThe expression of HOTAIR was detected in different tissues and cell lines by real-time PCR. Lentivirus-mediated HOTAIR-specific shRNAvectors were transfected into endometrial cancer HEC-1A cells. Cell proliferation and colony formation were examined by CCK-8 assays and colony formation assays, respectively. Invasion and migration were examined by Transwell assays. Flow cytometry assay was used to examine the cell cycle. In addition, xenograft model assays were performed to analyze the growth of endometrial cancer cells in vivo.ResultsOur data showed that HOTAIR expression was higher in endometrial cancer cells and tissues than in normal endometrial tissues. HOTAIR expression was closely related to the tumor stage (P= 0.045), myometrial invasion (P= 0.014), and lymph node metastasis (P= 0.033). The down-regulation of HOTAIR resulted in a significant inhibition of cell proliferation, migration, and invasion and in cell cycle arrest at the G0/G1 phase. Furthermore, HOTAIR depletion significantly suppressed the endometrial cancer tumorigenesis in vivo.ConclusionsThis study is the first to suggest that HOTAIR plays an important role in the carcinogenesis of endometrial cancer. Targeting HOTAIR may be a novel therapeutic strategy for endometrial cancer.

scholarly journals The Glutaminase Inhibitor Compound 968 Exhibits Potent in vitro and in vivo anti-tumor Effects in Endometrial Cancer

2020 ◽  
Author(s):  
Lingqin Yuan ◽  
Hui Guo ◽  
Guoyou Pan ◽  
Cong Wang ◽  
Dapeng Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Endometrial Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cellular Stress ◽  
Glutamine Metabolism ◽  
Pathway Inhibition

Abstract Background: Glutamine is one of the primary nutrients utilized by cancer cells for energy production and biosynthesis. Interfering with glutamine metabolism may impose anti-tumor effects. In this study, we aimed to investigated the anti-tumorigenic effects of GLS1 inhibition in endometrial cancer cells in vitro and in vivo. Methods: In this study, we assessed the relationship between glutaminase-1 enzyme (GLS1) expression and prognosis in endometrial cancer by bioinformatics analyses. Overall survival (OS) and progression-free survival (PFS) analyses were performed using the Kaplan-Meier method. The effects of compound 968 on cell proliferation, cell cycle, apoptosis, cellular stress, invasion, and AKT/mTOR/S6 pathway inhibition in human endometrial cancer cell lines were assessed. The in vivo therapeutic potential of compound 968 in endometrial cancer was evaluated using tumor xenografts.Results: We found that GLS1 expression is elevated during endometrial cancer progression and is associated with poor prognosis. The GLS1-targeting compound 968 was able to reduce cancer cell proliferation, induce cell cycle arrest at the G1 phase, inhibit cell invasion, as well as promote cellular stress and cancer cell apoptosis. Compound 968 treatment significantly increased the sensitivity of cells to paclitaxel. Moreover, the treatment of endometrial cancer cells with compound 968 resulted in AKT/mTOR/S6 signaling pathway inhibition. In xenograft mouse models of endometrial cancer, compound 968 significantly suppressed tumor growth. Conclusion: We conclude that compound 968 is a promising anti-tumorigenic agent and that combination with paclitaxel may be a valuable strategy for the treatment of endometrial cancer.

scholarly journals Ophiorrhiza Pumila Extract Exhibits Tumor-suppressive Activity in a Mouse Lymphoma Model

2021 ◽  
Author(s):  
Lixia Fan ◽  
Wanqin Liao ◽  
Zezhen Chen ◽  
Shaojing Li ◽  
Anping Yang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Mouse Model ◽  
Tumor Growth ◽  
Inhibitory Effect ◽  
Significant Inhibition ◽  
Cell Cycle Distribution ◽  
Dependent Manner ◽  
Cycle Arrest ◽  
Tumor Tissues

Abstract BackgroundRelapse and drug resistance of lymphomas are common, howerver the treatment efficacy of current therapeutic strategies remains unsatisfied. Our current study revealed that the extract of Ophiorrhiza pumila (OPE) has a potential anti-liver cancer activity. In this study, we aimed to investigate the effect of OPE on preventing lymphomas and explored the underlying mechanisms.MethodsCCK-8 assay was applied to detect the effect of OPE on cell proliferation. Flow cytometry was used to analyzed the effect of OPE on cell cycle distribution, and apoptosis. Xenograft mouse model was conducted to determine the anti-tumor activity of OPE. TNUEL assay was performed to detect the apoptosis in tumor tissues. Western blot and immunohistochemistry were used to determined protein expression.ResultsOPE decreased A20 cell proliferation in a dose- and time-dependent manner. OPE treatment induced cell cycle arrest at S phase and elevated apoptosis in A20 cells. Moreover, OPE displayed a significant inhibition in tumor growth in a mouse model. OPE increased apoptosis in tumor tissues revealed by TUNEL assay, which was companied with enhanced cleaved caspase 3 expression and Bax/Bcl2 ratio. In addition, our data showed that OPE suppressed A20 cell viability partially by reducing EGFR phosphorylation.ConclusionsOur data showed that OPE has an inhibitory effect on A20 cell proliferation and tumor growth, which is mediated by inactivation of EGFR and enhanced apoptosis.

scholarly journals GNA14 Stimulation of KLF7 Promotes Malignant Growth of Endometrial Cancer Through Upregulation of HAS2

2020 ◽  
Author(s):  
Jing Wang ◽  
Fei Teng ◽  
Hongxia Chai ◽  
Caixia Zhang ◽  
Xiaolei Liang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Endometrial Cancer ◽  
Tumor Growth ◽  
Colony Formation ◽  
Cell Biology ◽  
Loss Of Function ◽  
Α Subunit ◽  
And Migration

Abstract Background: Endometrial cancer (UCEC) is one of the most common gynecological malignancies. We previously found that G protein α subunit 14 (GNA14) was highly expressed in UCEC tissues and functioned as oncogene. Krüppel-like factors (KLFs) are transcription factors and play important roles in cancer development. However, the connection between GNA14 and KLF7 in UCEC are unclear. We herein explored the role of GNA14/KLF7 in UCEC development.Methods: Clinical relevance of GNA14, KLF7 and HAS2 in UCEC was analyzed from TCGA. siRNAs were used to knock down indicated genes. Lentivirus was used to perform overexpression. mRNA and protein expression was detected by qRT-PCR and Western blot. CCK8, colony formation, cell cycle, apoptosis, transwell and wound healing were performed to check cell biology function in vitro. Tumor growth in nude mice was conducted to check in vivo function. RNA sequencing was used to determined dys-regulated genes.Results: We demonstrated that GNA14 upregulation of KLF7 promoted UCEC carcinogenesis through activation of hyaluronan synthase 2 (HAS2). Firstly, GNA14 promoted the expression KLF7 in UCEC cells. GNA14 was positively correlated with KLF7 in normal and UCEC tissues based on TCGA database. Then, loss-of-function and gain-of-function assays showed that KLF7 promoted cell proliferation, colony formation, cell cycle progression, and migration of UCEC cells. Apoptosis was inhibited by KLF7. KLF7 knockdown also reduced xenografted tumor growth of UCEC cells. Furthermore, RNA sequence results showed that KLF7 regulated thousands of genes, among which HAS2 was downregulated in KLF7 knockdown cells. Based on TCGA database and immunoblotting assays, KLF7 positively regulated HAS2 in UCEC cells and tissues. Lastly, knockdown of HAS2 reversed the oncogenic role of KLF7 on UCEC cell proliferation and migration.Conclusion: Taken together, we reveal that GNA14/KLF7/HAS2 signaling cascade is a novel contributor to UCEC development.

scholarly journals Matrix degradation and cell proliferation are coupled to promote invasion and escape from an engineered human breast microtumor

2021 ◽  
Vol 13 (1) ◽  
pp. 17-29
Author(s):  
Emann M Rabie ◽  
Sherry X Zhang ◽  
Andreas P Kourouklis ◽  
A Nihan Kilinc ◽  
Allison K Simi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Type I ◽  
Matrix Degradation ◽  
Human Breast ◽  
Rate Of Invasion

Abstract Metastasis, the leading cause of mortality in cancer patients, depends upon the ability of cancer cells to invade into the extracellular matrix that surrounds the primary tumor and to escape into the vasculature. To investigate the features of the microenvironment that regulate invasion and escape, we generated solid microtumors of MDA-MB-231 human breast carcinoma cells within gels of type I collagen. The microtumors were formed at defined distances adjacent to an empty cavity, which served as an artificial vessel into which the constituent tumor cells could escape. To define the relative contributions of matrix degradation and cell proliferation on invasion and escape, we used pharmacological approaches to block the activity of matrix metalloproteinases (MMPs) or to arrest the cell cycle. We found that blocking MMP activity prevents both invasion and escape of the breast cancer cells. Surprisingly, blocking proliferation increases the rate of invasion but has no effect on that of escape. We found that arresting the cell cycle increases the expression of MMPs, consistent with the increased rate of invasion. To gain additional insight into the role of cell proliferation in the invasion process, we generated microtumors from cells that express the fluorescent ubiquitination-based cell cycle indicator. We found that the cells that initiate invasions are preferentially quiescent, whereas cell proliferation is associated with the extension of invasions. These data suggest that matrix degradation and cell proliferation are coupled during the invasion and escape of human breast cancer cells and highlight the critical role of matrix proteolysis in governing tumor phenotype.

scholarly journals The potential oncogenic and MLN4924-resistant effects of CSN5 on cervical cancer cells

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Huilin Zhang ◽  
Ping He ◽  
Qing Zhou ◽  
Yan Lu ◽  
Bingjian Lu
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cervical Cancer Cell ◽  
Cervical Cancers ◽  
Cervical Cancer Cells

Abstract Background CSN5, a member of Cop9 signalosome, is essential for protein neddylation. It has been supposed to serve as an oncogene in some cancers. However, the role of CSN5 has not been investigated in cervical cancer yet. Methods Data from TCGA cohorts and GEO dataset was analyzed to examine the expression profile of CSN5 and clinical relevance in cervical cancers. The role of CSN5 on cervical cancer cell proliferation was investigated in cervical cancer cell lines, Siha and Hela, through CSN5 knockdown via CRISPR–CAS9. Western blot was used to detect the effect of CSN5 knockdown and overexpression. The biological behaviors were analyzed by CCK8, clone formation assay, 3-D spheroid generation assay and cell cycle assay. Besides, the role CSN5 knockdown in vivo was evaluated by xenograft tumor model. MLN4924 was given in Siha and Hela with CSN5 overexpression. Results We found that downregulation of CSN5 in Siha and Hela cells inhibited cell proliferation in vitro and in vivo, and the inhibitory effects were largely rescued by CSN5 overexpression. Moreover, deletion of CSN5 caused cell cycle arrest rather than inducing apoptosis. Importantly, CSN5 overexpression confers resistance to the anti-cancer effects of MLN4924 (pevonedistat) in cervical cancer cells. Conclusions Our findings demonstrated that CSN5 functions as an oncogene in cervical cancers and may serve as a potential indicator for predicting the effects of MLN4924 treatment in the future.

scholarly journals Induction of apoptosis and cell cycle arrest by chloroform fraction of Juniperus phoenicea and chemical constituents analysis

2021 ◽  
Vol 19 (1) ◽  
pp. 119-127
Author(s):  
Ibrahim O. Barnawi ◽  
Fahd A. Nasr ◽  
Omar M. Noman ◽  
Ali S. Alqahtani ◽  
Mohammed Al-zharani ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Chloroform Fraction ◽  
Active Fraction ◽  
Cycle Arrest ◽  
Juniperus Phoenicea ◽  
Medicinal Properties ◽  
Mcf 7

Abstract Different phytochemicals from various plant species exhibit promising medicinal properties against cancer. Juniperus phoenicea is a plant species that has been found to present medicinal properties. Herein, crude extract and fractions of J. phoenicea were examined to determine its anticancer properties against several cancer cells. The active fraction was chosen to assess its activity on cell cycle progression and apoptosis induction by annexin and propidium iodide (PI) biomarkers. Further, phytochemical screening for possible contents of active fraction using gas chromatography–mass spectrometry (GC-MS) analysis was conducted. It was demonstrated that cell proliferation was suppressed, and the MCF-7 cell line was the most sensitive to J. phoenicea chloroform fraction (JPCF), with the IC50 values of 24.5 μg/mL. The anti-proliferation activity of JPCF in MCF-7 cells was linked to the aggregation of cells in the G1 phase, increases in early and late apoptosis as well as necrotic cell death. Contents analysis of JPCF using GC-MS analysis identified 3-methyl-5-(2′,6′,6′-trimethylcyclohex-1′-enyl)-1-penten-3-ol (16.5%), methyl 8-oxooctanoate (15.61%), cubenol (13.48%), and 7-oxabicyclo [2.2.1] heptane (12.14%) as major constituents. Our present study provides clear evidence that J. phoenicea can inhibit cell proliferation, trigger cell cycle arrest, and induce apoptosis in tested cancer cells.

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