scholarly journals The Role of GDF15 in Regulating the Canonical Pathways of the Tumor Microenvironment in Wild-Type p53 Ovarian Tumor and Its Response to Chemotherapy

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3043
Author(s):  
Daisy I. Izaguirre ◽  
Chun-Wai Ng ◽  
Suet-Yan Kwan ◽  
Eucharist H. Kun ◽  
Yvonne T. M. Tsang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Wild Type ◽  
Ovarian Cancer Cell Lines ◽  
Canonical Pathways ◽  
Wild Type P53

Background: The standard treatment of ovarian cancer is surgery followed by a chemotherapeutic combination consisting of a platinum agent, such as cisplatin and a taxane-like paclitaxel. We previously observed that patients with ovarian cancer wild-type for p53 had a poorer survival rate than did those with p53 mutations. Thus, a better understanding of the molecular changes of epithelial ovarian cancer cells with wild-type p53 in response to treatment with cisplatin could reveal novel mechanisms of chemoresistance. Methods: Gene expression profiling was performed on an ovarian cancer cell line A2780 with wild-type p53 treated with cisplatin. A gene encoding a secretory protein growth differentiation factor 15 (GDF15) was identified to be highly induced by cisplatin treatment in vitro. This was further validated in a panel of wild-type and mutant p53 ovarian cancer cell lines, as well as in mouse orthotopic models. The mouse tumor tissues were further analyzed by histology and RNA-seq. Results: GDF15 was identified as one of the highly induced genes by cisplatin or carboplatin in ovarian cancer cell lines with wild-type p53. The wild-type p53-induced expression of GDF15 and GDF15-confered chemotherapy resistance was further demonstrated in vitro and in vivo. This study also discovered that GDF15-knockdown (GDF15-KD) tumors had less stromal component and had different repertoires of activated and inhibited canonical pathways in the stromal cell and cancer cell components from that of the control tumors after cisplatin treatment. Conclusions: GDF15 expression from the wild-type p53 cancer cells can modulate the canonical pathways in the tumor microenvironment in response to cisplatin, which is a possible mechanism of chemoresistance.

The Novel IκB Kinase β Inhibitor, IMD-0560, Has Potent Therapeutic Efficacy in Ovarian Cancer Xenograft Model Mice

2016 ◽  
Vol 26 (4) ◽  
pp. 610-618 ◽  
Author(s):  
Ikuko Sawada ◽  
Kae Hashimoto ◽  
Kenjiro Sawada ◽  
Yasuto Kinose ◽  
Koji Nakamura ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Therapeutic Potential ◽  
Ovarian Cancer Cell Lines ◽  
Iκb Kinase ◽  
Xenograft Mice

ObjectiveAberrant activation of nuclear factor-kappa β (NF-κB) signaling has been correlated with poor outcome among patients with ovarian cancer. Although the therapeutic potential of NF-κB pathway disruption in cancers has been extensively studied, most classical NF-κB inhibitors are poorly selective, exhibit off-target effects, and have failed to be applied in clinical use. IMD-0560,N-[2,5-bis (trifluoromethyl) phenyl]-5-bromo-2-hydroxybenzamide, is a novel low-molecular-weight compound that selectively inhibits the IκB kinase complex and works as an inhibitor of NF-κB signaling. The aim of this study was to assess the therapeutic potential of IMD-0560 against ovarian cancer in vitro and in vivo.MethodsNF-κB activity (phosphorylation) was determined in 9 ovarian cancer cell lines and the inhibitory effect of IMD-0560 on NF-κB activation was analyzed by Western blotting. Cell viability, cell cycle, vascular endothelial growth factor (VEGF) expression, and angiogenesis were assessed in vitro to evaluate the effect of IMD-0560 on ovarian cancer cells. In vivo efficacy of IMD-0560 was also investigated using an ovarian cancer xenograft mouse model.ResultsThe NF-κB signaling pathway was constitutively activated in 8 of 9 ovarian cancer cell lines. IMD-0560 inhibited NF-κB activation and suppressed ovarian cancer cell proliferation by inducing G1 phase arrest. IMD-0560 decreased VEGF secretion from cancer cells and inhibited the tube formation of human umbilical vein endothelial cells. IMD-0560 significantly inhibited peritoneal metastasis and prolonged the survival in an ovarian cancer xenograft mice model. Immunohistochemical staining of excised tumors revealed that IMD-0560 suppressed VEGF expression, tumor angiogenesis, and cancer cell proliferation.ConclusionsIMD-0560 showed promising therapeutic efficacy against ovarian cancer xenograft mice by inducing cell cycle arrest and suppressing VEGF production from cancer cells. IMD-0560 may be a potential future option in regimens for the treatment of ovarian cancer.

scholarly journals Inhibition of MUS81 By siRNA Reverses Resistance to Cisplatin in Human Ovarian Cancer Cell Lines

2021 ◽  
Author(s):  
Emma C. Bourton ◽  
Sheba Adam-Zahir ◽  
Piers N. Plowman ◽  
Hussein Nahidh Al-Ali ◽  
Helen A. Foster ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Protein Expression ◽  
Cell Lines ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Cancer Cell Lines ◽  
Resistant Cell ◽  
Wild Type ◽  
Ovarian Cancer Cell Lines ◽  
Sirna Knockdown

Abstract Bacground: Drugs that induce DNA interstrand crosslinks form the mainstay of anticancer treatments for different cancers. These drugs are used to treat ovarian cancer which is the most prevalent gynaecological cancer. Five-year survival rates are approximately 40% and the development of drug resistant disease is an important factor in treatment failure. Methods: In this study a comprehensive evaluation of the expression and function of the site-specific endonuclease MUS81 was conducted. Using quantitative real time PCR analysis and imaging flow cytometry we determined the mRNA and protein expression of MUS81 in three ovarian cancer cell lines and two immortalised human fibroblast cell lines which had been made resistant to cisplatin by chronic exposure. siRNA knockdown of MUS81 was employed to determine the effect on overall cell survival which was assessed using clonogenic assays. Results: In the five cisplatin-resistant cell lines we observed increased MUS81 mRNA expression. In addition MUS81 protein expression in the form of discrete nuclear foci in cells was observed in all cell lines following cisplatin exposure, there being significantly more foci in cisplatin resistant cell lines. siRNA knockdown of MUS81 significantly reduced both mRNA and protein levels in two cell lines (SK-OV-3 and MRC5-SV1 – wild-type and resistant) and critically re-sensitised cisplatin resistant cells to wild-type level, determined by clonogenic assay.Conclusion: MUS81 is central to the development of cisplatin resistance in ovarian cancer cell lines. Inhibition of MUS81 restored drug sensitivity to the cells. MUS81 may be a useful therapeutic target to overcome drug resistance in ovarian and other cancers.

LncRNA SDHAP1 confers paclitaxel resistance of ovarian cancer by regulating EIF4G2 expression via miR-4465

2020 ◽  
Vol 168 (2) ◽  
pp. 171-181 ◽  
Author(s):  
Hui Zhao ◽  
Aixia Wang ◽  
Zhiwei Zhang
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Cancer Cell Lines ◽  
Regulatory Function ◽  
Ovarian Cancer Cells ◽  
Chemotherapeutic Resistance ◽  
Ovarian Cancer Cell Lines

Abstract Ovarian cancer has ranked as one of the leading causes of female morbidity and mortality around the world, which affects ∼239,000 patients and causes 152,000 deaths every year. Chemotherapeutic resistance of ovarian cancer remains a devastating actuality in clinic. The aberrant upregulation of long non-coding RNA succinate dehydrogenase complex flavoprotein subunit A pseudogene 1 (lncRNA SDHAP1) in the Paclitaxel (PTX)-resistant ovarian cancer cell lines has been reported. However, studies focussed on SDHAP1 in its regulatory function of chemotherapeutic resistance in ovarian cancer are limited, and the detailed mechanisms remain unclear. In this study, we demonstrated that SDHAP1 was upregulated in PTX-resistant SKOV3 and Hey-8 ovarian cancer cell lines while the level of miR-4465 was downregulated. Knocking-down SDHAP1 induced re-acquirement of chemo-sensitivity to PTX in ovarian cancer cells in vitro. Mechanically, SDHAP1 upregulated the expression of EIF4G2 by sponging miR-4465 and thus facilitated the PTX-induced apoptosis in ovarian cancer cells. The regulation network involving SDHAP1, miR-4465 and EIF4G2 could be a potential therapy target for the PTX-resistant ovarian cancer.

scholarly journals Palmatine from Unexplored Rutidea parviflora Showed Cytotoxicity and Induction of Apoptosis in Human Ovarian Cancer Cells

Toxins ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 237 ◽  
Author(s):  
Okiemute Rosa Johnson-Ajinwo ◽  
Alan Richardson ◽  
Wen-Wu Li
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Caspase 3 ◽  
Ovarian Cancer Cell ◽  
Cancer Cell Lines ◽  
Cross Resistance ◽  
Gas Liquid Chromatography ◽  
Ovarian Cancer Cell Lines

Ovarian cancer ranks amongst the deadliest cancers in the gynaecological category of cancers. This research work aims to evaluate in vitro anti-ovarian cancer activities and identify phytochemical constituents of a rarely explored plant species—Rutidea parviflora DC. The aqueous and organic extracts of the plant were evaluated for cytotoxicity using sulforhodamine B assay in four ovarian cancer cell lines and an immortalized human ovarian epithelial (HOE) cell line. The bioactive compounds were isolated and characterized by gas/liquid chromatography mass spectrometry and nuclear magnetic resonance spectroscopy. Caspase 3/7 activity assay, western blotting and flow cytometry were carried out to assess apoptotic effects of active compounds. The extracts/fractions of R. parviflora showed promising anti-ovarian cancer activities in ovarian cancer cell lines. A principal cytotoxic alkaloid was identified as palmatine whose IC50 was determined as 5.5–7.9 µM. Palmatine was relatively selective towards cancer cells as it was less cytotoxic toward HOE cells, also demonstrating interestingly absence of cross-resistance in cisplatin-resistant A2780 cells. Palmatine further induced apoptosis by increasing caspase 3/7 activity, poly-ADP-ribose polymerase cleavage, and annexin V and propidium iodide staining in OVCAR-4 cancer cells. Our studies warranted further investigation of palmatine and R. parviflora extracts in preclinical models of ovarian cancer.

scholarly journals Follicle-Stimulating Hormone Is an Autocrine Regulator of the Ovarian Cancer Metastatic Niche Through Notch Signaling

2018 ◽  
Vol 3 (2) ◽  
pp. 340-357 ◽  
Author(s):  
Sakshi Gera ◽  
Sandeep Kumar S. ◽  
Shalini N Swamy ◽  
Rahul Bhagat ◽  
Annapurna Vadaparty ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Notch Signaling ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Ovarian Cancer Cells ◽  
Fsh Receptor ◽  
Ovarian Cancer Cell Lines ◽  
Tumor Tissues

Abstract The association between the upregulated Notch and FSH signaling and ovarian cancer is well documented. However, their signaling has been investigated independently and only in the primary tumor tissues. The aim of this study was to investigate the interactive effects of FSH and Notch signaling on ovarian cancer proliferation, formation, and maintenance of disseminated ovarian cancer cells. The roles of Notch and FSH in ovarian cancer pathogenesis were investigated with ovarian cancer cell lines and specific antibodies against Notch and FSH receptor (FSHR). FSH upregulated Notch signaling and proliferation in ovarian cancer cells. High levels of FSH were detected in the ascites of patients with serous ovarian adenocarcinoma. Spheroids from the patients’ ascites, as well as the spheroids from ovarian cancer cell lines under low attachment culture conditions, expressed FSHβ subunit mRNA and secreted the hormone into the medium. In contrast, primary ovarian tumor tissues and cell line monolayers expressed very low levels of FSHβ. Ovarian cancer cell spheroids also exhibited higher expression of FSH receptor and Notch downstream genes than their monolayer counterparts. A combination of FSHR and Notch antagonistic antibodies significantly inhibited spheroid formation and cell proliferation in vitro. This study demonstrates that spheroids in ascites express and secrete FSH, which regulates cancer cell proliferation and spheroidogenesis through Notch signaling, suggesting that FSH is an autocrine regulator of cancer metastasis. Furthermore, Notch and FSHR are potential immunotherapeutic targets for ovarian cancer treatment.

Critical role of SEMA5A expression in invasion and metastasis of ovarian cancer cell

2014 ◽  
Vol 2 (4) ◽  
pp. 247-259
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Critical Role ◽  
Migration And Invasion ◽  
Ovarian Cancer Cells ◽  
Cancer Tissue ◽  
Invasion And Metastasis

Semaphorins are a large family of genes involved in the development and morphogenesis of the nervous system. SEMA5A has been reported as a bi-functional molecule, acting as both oncogene and tumor suppressor in different types of cancer. High expression levels of SEMA5A and its receptor, Plexin-B3, were associated with aggressiveness in pancreatic and prostate cancers. Our previous study in ovarian cancer metastasis indicates that FAK knock-down can suppress ovarian cancer cells migration and invasion. We hypothesized that SEMA5A expression promotes ovarian cancer invasion and metastasis. We investigated the expression of SEMA5A in patients with metastatic ovarian cancer (n = 43), localized tumor (n = 37) and normal ovarian tissue (n = 12) from non-malignant diseases as control with different histopathological characteristics. For Silencing of SEMA5A in vitro, we treated human ovarian cancer cells (OVCAR-3, A2780/CP70) with miR-27a and miR-27b. We observed significantly higher expression of SEMA5A protein (P= 0.001) in metastatic ovarian cancer tissue associated with poor overall survival outcomes compared to localized ovarian cancer and control. In vitro silencing of SEMA5A reduced migration and invasion of ovarian cancer cell. Our data offer opportunities for the therapeutic modulation and biomarker of metastatic ovarian cancer.

scholarly journals LHRH might act as a negative autocrine regulator of proliferation of human ovarian cancer

2000 ◽  
pp. 665-670 ◽  
Author(s):  
G Emons ◽  
S Weiss ◽  
O Ortmann ◽  
C Grundker ◽  
KD Schulz
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Ovarian Cancer Cells ◽  
Human Ovarian Cancer ◽  
Lhrh Agonists ◽  
Ovarian Cancer Cell Lines ◽  
Low Concentrations

OBJECTIVE: More than 80% of human ovarian cancers express LHRH and its receptor. The proliferation of human ovarian cancer cell lines is reduced by both LHRH agonists and antagonists. This study was designed to further clarify the possible biological function of this LHRH system. DESIGN: As LHRH agonists and antagonists uniformly reduce proliferation of human ovarian cancer in a dose-dependent way, the effect of low concentrations of authentic LHRH was studied. In addition, longer periods of treatment (up to 9 days) were analyzed. To assess the physiological role of LHRH produced by ovarian cancer cells it was neutralized by adequate concentrations of a specific LHRH antiserum. METHODS: Human ovarian cancer cells EFO-21 and EFO-27, which express LHRH and its receptor, were incubated for 1-9 days with increasing concentrations (1pmol/l to 10 micromol/l) of authentic LHRH or with concentrations of LHRH antiserum capable of neutralizing at least 1nmol/l LHRH. Proliferation was assessed by counting cells. RESULTS AND CONCLUSIONS: Authentic LHRH reduced time- and dose-dependently proliferation (by maximally mean+/-s.e.m. 32.7 +/- 4.4%, Newman-Keuls, P < 0.001) of both ovarian cancer cell lines. At very low concentrations (1pmol/l) a marginal reduction of proliferation or no effect was observed. A mitogenic effect of authentic LHRH was never detected. Treatment of ovarian cancer cell cultures with antiserum to LHRH significantly increased (up to mean+/-s.e.m. 121.0 +/- 2.8% of controls, Newman-Keuls P <0.001) proliferation of EFO-21 and EFO-27 cells. These findings suggest that LHRH produced by human ovarian cancer cells might act as a negative autocrine regulator of proliferation.

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