scholarly journals Unraveling Autocrine Signaling Pathways through Metabolic Fingerprinting in Serous Ovarian Cancer Cells

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1927
Author(s):  
Ji Hee Ha ◽  
Muralidharan Jayaraman ◽  
Revathy Nadhan ◽  
Srishti Kashyap ◽  
Priyabrata Mukherjee ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Glutamate Receptors ◽  
Cell Line ◽  
Aerobic Glycolysis ◽  
Metabolic Fingerprinting ◽  
Ovarian Cancer Cells ◽  
Epithelial Cell Line ◽  
Autocrine Signaling ◽  
Synthesis Inhibitor

Focusing on defining metabolite-based inter-tumoral heterogeneity in ovarian cancer, we investigated the metabolic diversity of a panel of high-grade serous ovarian carcinoma (HGSOC) cell-lines using a metabolomics platform that interrogate 731 compounds. Metabolic fingerprinting followed by 2-dimensional and 3-dimensional principal component analysis established the heterogeneity of the HGSOC cells by clustering them into five distinct metabolic groups compared to the fallopian tube epithelial cell line control. An overall increase in the metabolites associated with aerobic glycolysis and phospholipid metabolism were observed in the majority of the cancer cells. A preponderant increase in the levels of metabolites involved in trans-sulphuration and glutathione synthesis was also observed. More significantly, subsets of HGSOC cells showed an increase in the levels of 5-Hydroxytryptamine, γ-aminobutyrate, or glutamate. Additionally, 5-hydroxytryptamin synthesis inhibitor as well as antagonists of γ-aminobutyrate and glutamate receptors prohibited the proliferation of HGSOC cells, pointing to their potential roles as oncometabolites and ligands for receptor-mediated autocrine signaling in cancer cells. Consistent with this role, 5-Hydroxytryptamine synthesis inhibitor as well as receptor antagonists of γ-aminobutyrate and Glutamate-receptors inhibited the proliferation of HGSOC cells. These antagonists also inhibited the three-dimensional spheroid growth of TYKNU cells, a representative HGSOC cell-line. These results identify 5-HT, GABA, and Glutamate as putative oncometabolites in ovarian cancer metabolic sub-type and point to them as therapeutic targets in a metabolomic fingerprinting-based therapeutic strategy.

scholarly journals Forkhead Box Protein C2 Promotes Epithelial-Mesenchymal Transition, Migration and Invasion in Cisplatin-Resistant Human Ovarian Cancer Cell Line (SKOV3/CDDP)

2016 ◽  
Vol 39 (3) ◽  
pp. 1098-1110 ◽  
Author(s):  
Chanjuan Li ◽  
Hongjuan Ding ◽  
Jing Tian ◽  
Lili Wu ◽  
Yun Wang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Epithelial Mesenchymal Transition ◽  
Ovarian Cancer Cell Line ◽  
Cancer Cell Line ◽  
Ovarian Cancer Cells ◽  
Skov3 Cell ◽  
Mesenchymal Transition ◽  
Forkhead Box

Background/Aims: Forkhead Box Protein C2 (FOXC2) has been reported to be overexpressed in a variety of human cancers. However, it is unclear whether FOXC2 regulates epithelial-mesenchymal transition (EMT) in CDDP-resistant ovarian cancer cells. The aim of this study is to investigate the effects of FOXC2 on EMT and invasive characteristics of CDDP-resistant ovarian cancer cells and the underlying molecular mechanism. Methods: MTT, Western blot, scratch wound healing, matrigel transwell invasion, attachment and detachment assays were performed to detect half maximal inhibitory concentration (IC50) of CDDP, expression of EMT-related proteins and invasive characteristics in CDDP-resistant ovarian cancer cell line (SKOV3/CDDP) and its parental cell line (SKOV3). Small hairpin RNA (shRNA) was used to knockdown FOXC2 and analyze the effect of FOXC2 knockdown on EMT and invasive characteristics of SKOV3/CDDP cells. Also, the effect of FOXC2 upregulation on EMT and invasive characteristics of SKOV3 cells was analyzed. Furthermore, the molecular mechanism underlying FOXC2-regulating EMT in ovarian cancer cells was determined. Results: Compared with parental SKOV3 cell line, SKOV3/CDDP showed higher IC50 of CDDP (43.26μM) (P<0.01) and acquired EMT phenotype and invasive characteristics. Gain- and loss-of-function assays indicated that shRNA-mediated FOXC2 knockdown could reverse EMT and reduce the capacity of migration, invasion, attachment and detachment in SKOV3/CDDP cell line and upregulation of FOXC2 could induce the reverse effects in parental SKOV3 cell line. Furthermore, it was found that activation of ERK or AKT/GSK-3β signaling pathways was involved in FOXC2-promoting EMT in CDDP-resistant ovarian cancer cells. Conclusions: Taken together, these data demonstrate that FOXC2 may be a promoter of EMT phenotype in CDDP-resistant ovarian cancer cells and a potential therapeutic target for the treatment of advanced ovarian cancer.

ID: 45: EVALUATION OF CELLULAR MECHANISMS BY WHICH CINOBUFOTALIN INHIBITS OVARIAN CANCER CELL LINES FUNCTION

2016 ◽  
Vol 64 (4) ◽  
pp. 950.1-950 ◽  
Author(s):  
SH Afroze ◽  
DC Zawieja ◽  
R Tobin ◽  
C Peddaboina ◽  
MK Newell-Rogers ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Viability ◽  
Cancer Cells ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Cancer Cell Lines ◽  
Ovarian Cancer Cells ◽  
Ovarian Cancer Cell Lines

ObjectiveCinobufotalin (CINO), a cardiotonic steroid (CTS) or bufadienolide, is extracted from the skin secretions of the traditional Chinese medicine giant toads (Chan su). CINO has been used as a cardiotonic, diuretic and a hemostatic agent. Previously we have shown that CINO inhibits the cytotrophoblast cell function. Recently other study has shown that CINO inhibits A549, a lung cancer cell function. In this study, we assessed the effect of CINO on three different ovarian cancer cell lines; SK-OV-3, CRL-1978 and CRL-11731 to confirm whether the effect of CINO is cell specific.Study DesignWe evaluated the effect of CINO on three ovarian cancer cells SK-OV-3, CRL-1978, and CRL-11731 function in vitro. Each Cell lines were treated with different concentrations of CINO (0.1, 1, 5 and 10 µM). For each cell line cell proliferation, migration and invasion were measured by using a CellTiter Assay (Promega), Cytoselect Assay (Cell Biolabs) and by using a FluoroBlock Assay (BD) respectively. Proliferating Cell Nuclear Antigen (PCNA) was also evaluated in cell lysates of CINO treated these 3 ovarian cancer cells by western blot analysis. Cell Cycle arrest and Cell viability were determined by fluorescence-activated cell sorting (FACS) analysis. We also performed Annexin V staining on CINO treated these 3 ovarian cancer cell lines by immunofluorescence to evaluate the pro-apoptotic protein expression. In addition mitochondrial membrane potential has also been measured for all these 3 ovarian cell lines after CINO treatment using MMP kit, by FACS analysis.ResultsConcentration of CINO at 0.5 µM inhibit SK-OV-3, CRL-1978, and CRL-11731 ovarian cancer cells proliferation, migration and invasion without cell death and loss of cell viability but cell viability differs for each cell line. Each cell lines differ in response to CINO doses for PCNA expression as well as Annexin V pro-apoptotic protein expression. CINO decreases mitochondrial membrane potential for SK-OV-3 but for CRL-1978 and CRL-11731 increases in response to CINO treatment.ConclusionCINO is cell specific, as each cancer cell line responds differently. These data demonstrate that the mode of action of CINO is different on these 3 types of ovarian cancer cells.

scholarly journals The effect of iron on the expression levels of calcium related gene in cisplatin resistant epithelial ovarian cancer cells

2021 ◽  
Author(s):  
Bahire Kucukkaya ◽  
Demet Erdag ◽  
Fahri Akbas ◽  
Leman Yalcintepe
Keyword(s):  
Ovarian Cancer ◽  
Drug Resistance ◽  
Epithelial Ovarian Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Calcium Homeostasis ◽  
Ovarian Cancer Cell Line ◽  
Ovarian Cancer Cells ◽  
Gene Expressions ◽  
Iron Treatment

Aim: Anticancer drugs (chemotherapeutics) used in cancer treatment (chemotherapy) lead to drug resistance. This study was conducted to investigate the possible effect of iron on calcium homeostasis in epithelial ovarian cancer cells (MDAH-2774) and cisplatin-resistant cells of the same cell line (MDAH-2774/DDP). Methods: To develop MDAH-2774/DDP cells, MDAH-2774 (MDAH) cells were treated with cisplatin in dose increases of 5 μM between 0 μM and 70 μM. The effect of iron on the viability of MDAH and MDAH/DDP cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test at the end of 24 h incubation. Results: At increasing iron concentrations in MDAH and MDAH/DDP cells, the mRNA gene of fifteen genes [inositol 1,4,5-triphosphate receptor (IP3R)1/2/3, ryanodine receptor (RYR)1/2, sarco/endoplasmic reticulum Ca2+ ATPase (SERCA)1/2/3, Na+/Ca2+ exchange (NCX)1/2/3, and plasma membrane Ca2+ ATPase (PMCA)1/2/3/4] associated with Ca2+ differences in expression were determined by quantitative reverse transcription-polymerase chain reaction. Changes in IP3R2, RYR1, SERCA2, NCX3, PMCA1, and PMCA3 gene expressions were observed in iron treatment of MDAH/DDP cells, while changes were detected in iron treatment of MDAH cells in IP3R1/2/3, RYR1/2, SERCA1/2/3, NCX2/3, and PMCA1 expressions. Conclusions: This changes in the expression of calcium channels, pumps, and exchange proteins in the epithelial ovarian cancer cell line and in cisplatin-resistant epithelial ovarian cancer cells suggest that iron may have an important role in regulating calcium homeostasis. Due to differences in the expression of genes that play of an important role in the regulation of calcium homeostasis in the effect of iron, drug resistance can be prevented by introducing a new perspective on the use of inhibitors and activators of these genes and thus cytostatic treatment strategies.

scholarly journals 1-MT inhibits the invasion of CBP-resistant ovarian cancer cells via down-regulating IDO expression and re-activating immune cells function

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Huihan Ma ◽  
Qian Qin ◽  
Jiaqing Mi ◽  
Qinmei Feng
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Nk Cells ◽  
Cancer Cells ◽  
Cell Line ◽  
Cd8 T Cells ◽  
Ovarian Cancer Cells ◽  
Skov3 Cell ◽  
Conceptual Foundation ◽  
Tumor Immune Escape

Abstract Background The indoleamine 2, 3-dioxygenase (IDO) inhibitor 1-methyl-tryptophan (1-MT) is currently being used in clinical trials in patients with relapsed or refractory solid tumors by inhibiting tumor immune escape. A greater understanding of IDO activity is required to begin to understand the molecular mechanism by which drugs work. This study was conducted to investigate of the clinical significance of 1-methyl-tryptophan (1-MT) in treating carboplatin-resistant (CBP-resistant) ovarian cancer and its mechanism of action. Methods Using a medium dose, intermittent treatment method, a clinically relevant CBP-resistant human ovarian cancer cell line (SKOV3/CBP) was established. SKOV3/CBP cells were treated with normal serum (control) or 1-MT (0.25 ng/mL) for 4 h (SKOV3/CBP + 1-MT). Cell proliferation, invasion and IDO expression in SKOV3, SKOV3/CBP and SKOV3/CBP + 1-MT cells were determined by MTT assays, Matrigel invasion chambers assays and ELISAs, respectively. The half-maximal inhibitory concentration (IC50) and resistance index (RI) were also calculated. The killing ability of the NK cells and CD8+ T cells co-cultured with SKOV3, SKOV3/CBP and SKOV3/CBP + 1-MT cells were determined by LDH activity assays and the INF-γcounting method. Results The SKOV3/CBP cell line displayed an increased IC50 compared to the SKOV3 cell line (P < 0.05) under CBP treatment. Treatment with 1-MT significantly decreased the IC50 and RI of SKOV3/CBP cells. Furthermore, 1-MT treatment not only reduced the invasion ability, but also suppressed IDO expression in the drug-resistant SKOV3/CBP + 1-MT cell line as compared to the SKOV3/CBP cell line. Furthermore, 1-MT enhanced the killing ability of NK cells and the amount of INF-γsecreted from CD8+ T cells which were co-cultured with the SKOV3/CBP cell line. Conclusion Our data suggested that 1-MT inhibits the invasion of CBP-resistant ovarian cancer cells via down-regulation of IDO expression which leads to re-activation of immune cell function. We provide a conceptual foundation for the clinical development of 1-MT as an anti-tumor immunomodulator for chemotherapy resistant ovarian cancer patients.

scholarly journals Forkhead Box Protein C2 (FOXC2) Promotes the Resistance of Human Ovarian Cancer Cells to Cisplatin In Vitro and In Vivo

2016 ◽  
Vol 39 (1) ◽  
pp. 242-252 ◽  
Author(s):  
Chanjuan Li ◽  
Hongjuan Ding ◽  
Jing Tian ◽  
Lili Wu ◽  
Yun Wang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Mapk Signaling ◽  
Ovarian Cancer Cells ◽  
Human Ovarian Cancer ◽  
Cancer Tissues ◽  
Mapk Signaling Pathways

Background/Aims: FOXC2 has been reported to play a role in tumor progression, but the correlations of FOXC2 with the cisplatin (CDDP) resistance of ovarian cancer cells are still unclear. The purpose of the present study is to investigate the roles of FOXC2 in the CDDP resistance of ovarian cancer cells and its possible mechanisms. Methods: Quantitative real-time PCR (qRT-PCR) was performed to detect the expression of FOXC2 mRNA in CDDP-resistant or sensitive ovarian cancer tissues and cell lines (SKOV3/CDDP and SKOV3). Gain- and loss-of-function assays were performed to analyze the effects of FOXC2 knockdown or overexpression on the in vitro and in vivo sensitivity of ovarian cancer cells to CDDP and its possible molecular mechanisms. Results: The relative expression level of FOXC2 mRNA in CDDP-resistant ovarian cancer tissues was higher than that in CDDP-sensitive tissues. Also, the expression of FOXC2 mRNA and protein in CDDP-resistant ovarian cancer cell line (SKOV3/CDDP) cell line was higher than that in its parental cell line (SOKV3). Small hairpin RNA (shRNA)-mediated FOXC2 knockdown significantly increased the in vitro and in vive sensitivity of SKOV3/CDDP cells to CDDP by enhancing apoptosis, while upregulation of FOXC2 significantly decreased the in vitro and in vivo sensitivity of SKOV3 cells to CDDP by reducing apoptosis. Furthermore, FOXC2 activates the Akt and MAPK signaling pathways, and then induced the decreased expression of Bcl-2 protein and the increased expression of Bax and cleaved caspase-3 proteins. Conclusions: FOXC2 mediates the CDDP resistance of ovarian cancer cells by activation of the Akt and MAPK signaling pathways, and may be a potential novel therapeutic target for overcoming CDDP resistance in human ovarian cancer.

scholarly journals HDAC1 Silencing in Ovarian Cancer Enhances the Chemotherapy Response

2018 ◽  
Vol 48 (4) ◽  
pp. 1505-1518 ◽  
Author(s):  
Xinfeng Liu ◽  
Ying Yu ◽  
Jinna Zhang ◽  
Caixia Lu ◽  
Liming Wang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cell Line ◽  
Cisplatin Resistance ◽  
Ovarian Cancer Cells ◽  
Xenograft Tumor ◽  
Underlying Mechanisms ◽  
Xenograft Tumor Growth

Background/Aims: Cisplatin-based treatment is first-line chemotherapy for several cancers including ovarian cancer. The development of cisplatin resistance results in treatment failure, but the underlying mechanisms are not fully understood. Histone deacetylases (HDACs) are a large family of enzymes that deacetylate lysine residues on histones and non-histone proteins. High expression of HDAC1 is associated with poor outcomes in ovarian cancer. Furthermore, resistance to chemotherapeutic agents is associated with HDAC1 overexpression in ovarian cancer cells. The goals of this study were to determine whether targeting HDAC1 can sensitize ovarian cancer cells to cisplatin and to explore the underlying mechanisms. Methods: Small interfering RNA (siRNA)-targeting HDAC1 was designed to silence HDAC1 in the cisplatin-resistant ovarian cancer cell line A2780CDDP and its cisplatin-sensitive cell line A2780. The effects of targeting HDAC1 on cell viability assay, colony formation, and apoptosis were detected. c-Myc re-expression or miR-34a inhibitors were used to examine the relationship among HDAC1, c-Myc, and miR-34a expression, which was assessed by western blot analysis and quantitative reverse transcription PCR. We established stable transfectants of A2780CDDP/HDAC1 short hairpin RNA (shRNA) and A2780/HDAC1 shRNA. The therapeutic effectiveness of cisplatin in murine xenograft models was assessed following shRNA-mediated HDAC1 silencing in A2780CDDP and A2780 cells. The mechanism of cell death was studied in tumor sections obtained from different mouse tumors. Results: In cisplatin-resistant A2780CDDP cells, HDAC1 knockdown by siRNA suppressed cell proliferation, and increased apoptosis and chemosensitivity by downregulating c-Myc and upregulating miR-34a. In cisplatin-sensitive A2780 cells, HDAC1 knockdown did not affect cell proliferation and apoptosis. Cisplatin treatment activated HDAC1 and c-Myc and inactivated miR-34a. Inhibition of HDAC1 with siRNA reduced c-Myc expression, increased miR-34a expression, and sensitized A2780 cells to cisplatin-induced apoptosis. c-Myc re-expression or miR-34a targeting by miR-34a inhibitors protected cells from apoptosis or reversed cisplatin resistance following HDAC1 knockdown or/and cisplatin exposure. Finally, in vivo studies showed that targeting HDAC1 inhibited A2780CDDP-induced xenograft tumor growth but not A2780-induced xenograft tumor growth. Targeting HDAC1 sensitized both A2780- and A2780CDDP-induced xenograft tumors to cisplatin treatment. Conclusions: Upregulation of HDAC1 is a crucial event in the development of drug resistance to current treatments in ovarian cancer. Thus, targeting HDAC1 by enhancing c-Myc-dependent miR-34a expression might be an effective strategy for increasing the efficacy of cisplatin treatment.

ATR-FTIR spectroscopy shows changes in ovarian cancer cells after incubation with novel organoamidoplatinum(ii) complexes

The Analyst ◽  
2018 ◽  
Vol 143 (24) ◽  
pp. 6087-6094 ◽  
Author(s):  
Khansa Al-Jorani ◽  
Anja Rüther ◽  
Rukshani Haputhanthri ◽  
Glen B. Deacon ◽  
Hsiu Lin Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Ftir Spectroscopy ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Ovarian Cancer Cell Line ◽  
Cancer Cell Line ◽  
Ovarian Cancer Cells ◽  
Line P

ATR-FTIR spectroscopy has been applied to compare the effect of new organoamidoplatinum(ii) complexes with cisplatin on cells from a cisplatin-sensitive and a cisplatin-resistant ovarian cancer cell line.

scholarly journals Tankyrase Promotes Aerobic Glycolysis and Proliferation of Ovarian Cancer through Activation of Wnt/β-Catenin Signaling

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Hong-Yi Yang ◽  
Jin-Xing Shen ◽  
Yi Wang ◽  
Yu Liu ◽  
Dong-Yan Shen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Lung Tumor ◽  
Aerobic Glycolysis ◽  
Hepatocellular Cancer ◽  
Drug Susceptibility ◽  
Ovarian Cancer Cells ◽  
Human Lung Tumor ◽  
Consumption Rates

Tankyrase (TNKS) plays important roles in the malignancy of several cancers such as human lung tumor, breast cancer, and hepatocellular cancer. However, its exact functions and molecular mechanisms in ovarian cancer remain unclear. In this study, we found that TNKS was aberrantly overexpressed in human ovarian cancer tissues and associated with poor patient prognosis. TNKS inhibition or knockdown not only reduced ovarian cancer cell proliferation, colony formation, migration, invasion, and tumorigenic potential in nude mice but also enhanced the drug susceptibility of ovarian cancer cells through arresting cell cycle and inducing apoptosis. These phenotypic changes correlated with downregulation of targets (Cyclin D1, MDR, and MMP-9) of Wnt/β-catenin signaling. Furthermore, downregulation of TNKS suppressed the glucose uptake, lactate excretion, and cellular ATP levels and increased cellular O2consumption rates. Molecular mechanism studies revealed that TNKS promoted aerobic glycolysis at least in part due to upregulation of pyruvate carboxylase (PC) via activation of Wnt/β-catenin/snail signaling. In agreement with these findings, expression of TNKS is positively associated with snail and PC in clinical ovarian cancer samples. Our findings identified TNKS as an oncogenic regulator of ovarian cancer cells proliferation that promotes aerobic glycolysis via activation of Wnt/β-catenin signaling, indicating that the TNKS might serve as a potential molecular target for clinical therapy of Wnt/β-catenin dependent ovarian cancer.

scholarly journals Long non-coding RNA GEHT1 promoted the proliferation of ovarian cancer cells via modulating the protein stability of HIF1α

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Dan Liu ◽  
Hao Li
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Aerobic Glycolysis ◽  
Hypoxia Inducible Factor ◽  
Ovarian Cancer Cells ◽  
Von Hippel Lindau ◽  
Non Coding Rna ◽  
Glycolysis Pathway ◽  
Cancer Tissues ◽  
Long Non Coding Rna

Abstract Cancer cells preferentially metabolize glucose via the aerobic glycolysis pathway, which is also named as Warburg effect. Increasing evidence has suggested that suppression of glycolysis inhibits the progression of cancers. In the present study, we found that the long non-coding RNA gastric carcinoma high expressed transcript 1 (GHET1) was overexpressed in ovarian cancer tissues and cell lines. Up-regulation of GHET1 was positively correlated with the tumor size and metastasis of the ovarian cancer patients. Overexpression of GEHT1 significantly promoted the proliferation and colony formation of ovarian cancer cells. Mechanistically, the candidate binding partners of GHET1 were explored by pull-down and mass spectrum. Of note, GHET1 was found to interact with the E3 ubiquitin ligase von Hippel-Lindau (VHL), which consequently blocked VHL-mediated degradation of hypoxia-inducible factor-1α (HIF1α) and enhanced the protein level of HIF1α in ovarian cancer cells. The up-regulated HIF1α promoted the glucose uptake and lactate generation of ovarian cancer cells. Collectively, our results suggested the oncogenic function of GHET1 via up-regulating the glycolysis in ovarian cancer and can be considered as a promising anti-cancer target.

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