Difluoromethylornithine Induces Apoptosis through Regulation of AP-1 Signaling via JNK Phosphorylation in Epithelial Ovarian Cancer

Difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), has promising activity against various cancers and a tolerable safety profile for long-term use as a chemopreventive agent. However, the anti-tumor effects of DFMO in ovarian cancer cells have not been entirely understood. Our study aimed to identify the effects and mechanism of DFMO in epithelial ovarian cancer cells using SKOV-3 cells. Treatment with DFMO resulted in a significantly reduced cell viability in a time- and dose-dependent manner. DFMO treatment inhibited the activity and downregulated the expression of ODC in ovarian cancer cells. The reduction in cell viability was reversed using polyamines, suggesting that polyamine depletion plays an important role in the anti-tumor activity of DFMO. Additionally, significant changes in Bcl-2, Bcl-xL, Bax protein levels, activation of caspase-3, and cleavage of poly (ADP-ribose) polymerase were observed, indicating the apoptotic effects of DFMO. We also found that the effect of DFMO was mediated by AP-1 through the activation of upstream JNK via phosphorylation. Moreover, DFMO enhanced the effect of cisplatin, thus showing a possibility of a synergistic effect in treatment. In conclusion, treatment with DFMO alone, or in combination with cisplatin, could be a promising treatment for ovarian cancer.

Download Full-text

Aspirin Blocks EGF-stimulated Cell Viability in a COX-1 Dependent Manner in Ovarian Cancer Cells

Journal of Cancer ◽

10.7150/jca.7118 ◽

2013 ◽

Vol 4 (8) ◽

pp. 671-678 ◽

Cited By ~ 11

Author(s):

May Cho ◽

Syeda M. Kabir ◽

Yuanlin Dong ◽

Eunsook Lee ◽

Valerie Montgomery Rice ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Viability ◽

Cancer Cells ◽

Ovarian Cancer Cells ◽

Dependent Manner ◽

Cox 1

Download Full-text

Acylated Ghrelin Renders Chemosensitive Ovarian Cancer Cells Resistant to Cisplatin Chemotherapy via Activation of the PI3K/Akt/mTOR Survival Pathway

Analytical Cellular Pathology ◽

10.1155/2019/9627810 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Attalla Farag El-kott ◽

Ali A. Shati ◽

Mohammed Ali Al-kahtani ◽

Sultan Alqahtani

Keyword(s):

Ovarian Cancer ◽

Cell Viability ◽

Cancer Cells ◽

Control Cell ◽

Nuclear Accumulation ◽

Ovarian Cancer Cells ◽

Apoptotic Pathway ◽

Ghrelin Receptor ◽

Protein Levels ◽

Ghrelin Receptor Antagonist

This study investigated the effect of acylated synthetic ghrelin (AG) on the survival and proliferation of human chemosensitive ovarian cancer cells (A2780) and explored some mechanisms of action with a focus on the p53 apoptotic pathway and PI3K/Akt and NF-κB survival pathways. Human A2780 ovarian cancer cells were cultured with or without AG treatment in the presence or absence of cisplatin. In some cases, cisplatin+AG-treated cells were pre-incubated either with [D-Lys3]-GHRP-6, a ghrelin receptor antagonist, or with LY294002, a PI3K inhibitor. mRNA of ghrelin receptors(GHS-R1a and GHS-R1b), as well as, protein levels of GHS-R1a, were expressed abundantly in A2780 cells. AG treatment did not affect the mRNA and protein levels of GHS-R1a and GHS-R1b in both control and Cis-treated cells. However, while AG treatment had no effect on control cell viability, it significantly increased cell viability and proliferation and inhibited cell death in Cis-treated cells. In both control and Cis-treated cells, AG treatment significantly increased PI3K/Akt/mTOR signaling and enhanced the nuclear accumulation of NF-κB. Concomitantly, in both control and Cis-treated cells, AG significantly lowered the protein levels of p53, p-p53 (Ser16), PUMA, cytochrome C, and cleaved caspase-3. Interestingly, pre-incubating the cells with either [D-Lys3]-GHRP-6 or LY294002 completely abolished the above-mentioned effect of AG in both control and Cis-treated cells. In conclusion, the findings of this study show that AG promotes cell survival of the OC cells and renders them resistat to Cis therapy, an effect that is mediated by the activation of PI3K/Akt/mTOR and activation of NF-κB, and requires GHS-R1a.

Download Full-text

222 ANTIFUNGAL AGENTS AS AGRICULTURAL PRODUCTS, FENHEXAMID, FLUDIOXONIL, AND CYPRODINIL, INDUCED THE EXPRESSION OF CYTOCHROME P450 FAMILY AND CELL CYCLE-RELATED GENES IN ESTROGEN RECEPTOR EXPRESSING BG-1 OVARIAN CANCER CELLS

Reproduction Fertility and Development ◽

10.1071/rdv27n1ab222 ◽

2015 ◽

Vol 27 (1) ◽

pp. 201

Author(s):

R.-E. Go ◽

K.-C. Choi

Keyword(s):

Ovarian Cancer ◽

Cell Viability ◽

Cyclin D1 ◽

Cancer Cells ◽

Antifungal Agents ◽

Negative Control ◽

Ovarian Cancer Cells ◽

Dependent Manner ◽

Environmental Carcinogens ◽

Expression Levels

Fenhexamid, fludioxonil, and cyprodinil are antifungal agents used in agricultural applications, which are present at measurable amounts in fruits and vegetables. The induction of CYP gene expression including CYP1A1 and CYP1B1 is mediated by the transformation of polycyclic aromatic hydrocarbons (PAHs), and modulated by aryl hydrocarbon receptor (AhR). CYP1A1 is expressed in the liver, pancreas, thymus, uterus, and small intestine. CYP1B1 is abundant in the prostate, breast, and uterus. Expression levels of CYP1A1 and CYP1B1 indicate PAH-induced immunotoxicity, oxidative stress, and activation of environmental carcinogens. In this study, the ability of cell viability was examined as MTT assay by pesticides; fenhexamid, fludioxonil and cyprodinil. In addition, expression levels of mRNA and protein of AhR, CYP1A1, and Cyclin D1 were analysed by RT-PCR and Western blot analysis in BG-1 ovarian cancer cells with oestrogen receptors (ER). To evaluate the ability of cell viability, BG-1 cells were cultured with a negative control (0.1% DMSO), 17β-oestradiol (E2; 1 × 10–9 M), fenhexamid, fludioxonil or cyprodinil (10–5–10–8 M). To evaluate the expression levels of mRNA and protein, BG-1 cells were cultured with a negative control (0.1% DMSO), 17β-oestradiol (E2; 10–9 M) and these pesticides (10–5 M). As results, E2 as a positive control markedly increased BG-1 cell viability ~5 times compared to a negative control (P < 0.05). In addition, treatments with these pesticides increased BG-1 cell viability at the concentrations of 10–8 and 10–5 M about from 1.5 to 2 times, respectively (P < 0.05). When respective treatment co-treated with ICI 182 780, an ER antagonist, BG-1 cell viability was reversed to the level of a negative control. The mRNA expression of CYP1A1 was increased by E2, fenhexamid, and cyprodinil in a time-dependent manner but not by fludioxonil, while its level was reversed in the presence of ICI 182 780. In parallel with their transcriptional levels, protein levels of CYP1A1 and cyclin D1 were induced by E2 and these pesticides, while the level of AhR was not altered by E2 and these pesticides. Taken together, these results imply that the pesticides, fenhexamid, fludioxonil, and cyprodinil, may have disruptive effects on ER expressing cells or tissues by alteration of CYP1A1 and cyclin D1 via an ER-dependent pathway.

Download Full-text

NGF-Enhanced Vasculogenic Properties of Epithelial Ovarian Cancer Cells Is Reduced by Inhibition of the COX-2/PGE2 Signaling Axis

Cancers ◽

10.3390/cancers11121970 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1970 ◽

Cited By ~ 6

Author(s):

Maritza P. Garrido ◽

Iván Hurtado ◽

Manuel Valenzuela-Valderrama ◽

Renato Salvatierra ◽

Andrea Hernández ◽

...

Keyword(s):

Ovarian Cancer ◽

Growth Factor ◽

Epithelial Ovarian Cancer ◽

Cell Lines ◽

Ovarian Cancer Cells ◽

Dependent Manner ◽

Protein Levels ◽

Angiogenic Proteins ◽

Signaling Axis ◽

Cox 2

Epithelial ovarian cancer (EOC) is a lethal gynecological neoplasia characterized by extensive angiogenesis and overexpression of nerve growth factor (NGF). Here, we investigated the mechanism by which NGF increases vascular endothelial growth factor (VEGF) expression and the vasculogenic potential of EOC cells, as well as the contribution of the cyclooxygenase 2/prostaglandin E2 (COX-2/PGE2) signaling axis to these events. EOC biopsies and ovarian cell lines were used to determine COX-2 and PGE2 levels, as well as those of the potentially pro-angiogenic proteins c-MYC (a member of the Myc transcription factors family), survivin, and β-catenin. We observed that COX-2 and survivin protein levels increased during EOC progression. In the EOC cell lines, NGF increased the COX-2 and PGE2 levels. In addition, NGF increased survivin, c-MYC, and VEGF protein levels, as well as the transcriptional activity of c-MYC and β-catenin/T-cell factor/lymphoid enhancer-binding factor (TCF-Lef) in a Tropomyosin receptor kinase A (TRKA)-dependent manner. Also, COX-2 inhibition prevented the NGF-induced increases in these proteins and reduced the angiogenic score of endothelial cells stimulated with conditioned media from EOC cells. In summary, we show here that the pro-angiogenic effect of NGF in EOC depends on the COX-2/PGE2 signaling axis. Thus, inhibition COX-2/PGE2 signaling will likely be beneficial in the treatment of EOC.

Download Full-text

Guizhi Fuling Wan, a Traditional Chinese Herbal Formula, Sensitizes Cisplatin-Resistant Human Ovarian Cancer Cells through Inactivation of the PI3K/AKT/mTOR Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/4651949 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 5

Author(s):

Li Han ◽

Xiaojuan Guo ◽

Hua Bian ◽

Lei Yang ◽

Zhong Chen ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Mtor Pathway ◽

Cell Counting ◽

Ovarian Cancer Cells ◽

Dependent Manner ◽

Bioactive Constituents ◽

Anticancer Efficacy ◽

Protein Levels ◽

And Function

The aim of the study was to explore the possible mechanisms that Guizhi Fuling Wan (GFW) enhances the sensitivity of the SKOV3/DDP ovarian cancer cells and the resistant xenograft tumours to cisplatin. Rat medicated sera containing GFW were prepared by administering GFW to rats, and the primary bioactive constituents of the sera were gallic acid, paeonol, and paeoniflorin analysed by HPLC/QqQ MS. Cell counting kit-8 analysis was shown that coincubation of the sera with cisplatin/paclitaxel enhanced significantly the cytotoxic effect of cisplatin or paclitaxel in SKOV3/DDP cells. The presence of the rat medicated sera containing GFW resulted in an increase in rhodamine 123 accumulation by flow cytometric assays and a decrease in the protein levels of P-gp, phosphorylation of AKT at Ser473, and mTOR in a dose-dependent manner in SKOV3/DDP cells by western blot analysis, but the sera had no effect on the protein levels of PI3K p110αand total AKT. The low dose of GFW enhanced the anticancer efficacy of cisplatin and paclitaxel treatment in resistant SKOV3/DDP xenograft tumours. GFW could sensitize cisplatin-resistant SKOV3/DDP cells by inhibiting the protein level and function of P-gp, which may be medicated through inactivation of the PI3K/AKT/mTOR pathway.

Download Full-text

ROS production is required for follicle-stimulating hormone-induced Nrf2 activation in human epithelial ovarian cancer cells

Academic Journal of Second Military Medical University ◽

10.3724/sp.j.1008.2012.00935 ◽

2013 ◽

Vol 32 (9) ◽

pp. 935-939

Author(s):

Jie MA ◽

Qian-qian WANG ◽

Hong LIAO ◽

Yong-bin YANG ◽

Zhi-jun JIN ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Cancer Cells ◽

Follicle Stimulating Hormone ◽

Ovarian Cancer Cells ◽

Ros Production ◽

Nrf2 Activation ◽

Stimulating Hormone

Download Full-text

Lupeol Inhibits Proliferation and Promotes Apoptosis of Ovarian Cancer Cells by Inactivating Phosphoinositide-3-Kinase/Protein Kinase B/ Mammalian Target of Rapamycin Pathway

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.19:206-210 ◽

2020 ◽

Vol 19 (2) ◽

pp. 206-210

Author(s):

Feng Chen ◽

Bei Zhang

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Protein Kinase ◽

Cell Viability ◽

Cancer Cells ◽

Protein Kinase B ◽

Mammalian Target Of Rapamycin ◽

Target Of Rapamycin ◽

Ovarian Cancer Cells ◽

Phosphoinositide 3 Kinase

Lupeol exhibits multiple pharmacological activities including, anticancerous, anti-inflammatory, and antioxidant. The aim of this study was to explore the anticancerous activity of lupeol on ovarian cancer cells and examine its mechanism of action. To this end, increasing concentrations of lupeol on cell viability, cell cycle, and apoptosis in Caov-3 cells were evaluated. Lupeol inhibited cell viability, induced G1 phase arrest in cell cycle, increased cell apoptosis, and inhibited the ratio of phospho-Akt/protein kinase B and phospho-mammalian target of rapamycin/mammalian target of rapamycin. In conclusion, these data suggest that lupeol may play a therapeutic role in ovarian cancer.

Download Full-text

Propofol suppresses cell viability, cell cycle progression and motility and induces cell apoptosis of ovarian cancer cells through suppressing MEK/ERK signaling via targeting circVPS13C/miR-145 axis

Journal of Ovarian Research ◽

10.1186/s13048-021-00775-3 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Huan Lu ◽

Guanlin Zheng ◽

Xiang Gao ◽

Chanjuan Chen ◽

Min Zhou ◽

...

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Cancer Cells ◽

Rna Binding ◽

Erk Signaling ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Ovarian Cancer Cells ◽

Dependent Manner ◽

Vacuolar Protein

Abstract Background Propofol is a kind of common intravenous anaesthetic agent that plays an anti-tumor role in a variety of cancers, including ovarian cancer. However, the working mechanism of Propofol in ovarian cancer needs further exploration. Methods The viability and metastasis of ovarian cancer cells were assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and transwell assays. Flow cytometry was used to evaluate the cell cycle and apoptosis. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to examine the abundance of circular RNA vacuolar protein sorting 13 homolog C (circVPS13C) and microRNA-145 (miR-145). The target relationship between miR-145 and circVPS13C was predicted by circinteractome database and verified by dual-luciferase reporter assay, RNA-binding protein immunoprecipitation (RIP) assay and RNA-pull down assay. Western blot assay was used to detect the levels of phosphorylated extracellular regulated MAP kinase (p-ERK), ERK, p-MAP kinse-ERK kinase (p-MEK) and MEK, in ovarian cancer cells. Results Propofol treatment suppressed the viability, cell cycle and motility and elevated the apoptosis rate of ovarian cancer cells. Propofol up-regulated miR-145 in a dose-dependent manner. Propofol exerted an anti-tumor role partly through up-regulating miR-145. MiR-145 was a direct target of circVPS13C. Propofol suppressed the progression of ovarian cancer through up-regulating miR-145 via suppressing circVPS13C. Propofol functioned through circVPS13C/miR-145/MEK/ERK signaling in ovarian cancer cells. Conclusion Propofol suppressed the proliferation, cell cycle, migration and invasion and induced the apoptosis of ovarian cancer cells through circVPS13C/miR-145/MEK/ERK signaling in vitro.

Download Full-text