Piperine Targets Different Drug Resistance Mechanisms in Human Ovarian Cancer Cell Lines Leading to Increased Sensitivity to Cytotoxic Drugs

Our goal was to examine the anticancer effects of piperine against the resistant human ovarian cancer cells and to explore the molecular mechanisms responsible for its anticancer effects. Our study used drug-sensitive ovarian cancer cell line W1 and its sublines resistant to paclitaxel (PAC) and topotecan (TOP). We analyzed the cytotoxic effect of piperine and cytostatic drugs using an MTT assay. The impact of piperine on protein expression was determined by immunofluorescence and Western blot. We also examined its effect on cell proliferation and migration. We noticed a different level of piperine resistance between cell lines. Piperine increases the cytotoxic effect of PAC and TOP in drug-resistant cells. We observed an increase in PTPRK expression correlated with decreased pTYR level after piperine treatment and downregulation of P-gp and BCRP expression. We also noted a decrease in COL3A1 and TGFBI expression in investigated cell lines and increased COL3A1 expression in media from W1PR2 cells. The expression of Ki67 protein and cell proliferation rate decreased after piperine treatment. Piperine markedly inhibited W1TR cell migration. Piperine can be considered a potential anticancer agent that can increase chemotherapy effectiveness in cancer patients.

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miR-214 promotes radioresistance in human ovarian cancer cells by targeting PETN

Bioscience Reports ◽

10.1042/bsr20170327 ◽

2017 ◽

Vol 37 (4) ◽

Cited By ~ 12

Author(s):

Qin Zhang ◽

Shuxiang Zhang

Keyword(s):

Ovarian Cancer ◽

Ionizing Radiation ◽

Cell Lines ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Cancer Cell Lines ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Ovarian Cancer Cell Lines ◽

Cancer Tissues

Ovarian cancer is one of the leading causes of death among gynecological malignancies. Increasing evidence indicate that dysregulation of microRNAs (miRNAs) plays an important role in tumor radioresistance. The aim of the present study is to investigate whether microRNA-214 (miR-214) was involved in radioresistance of human ovarian cancer. Here, we showed that miR-214 was significantly up-regulated in ovarian cancer tissues and radioresistance ovarian cancer cell lines. Transfection of miR-214 agomir in radiosensitive ovarian cancer cell lines promoted them for resistance to ionizing radiation, whereas transfection of miR-214 antagomir in radioresistance ovarian cancer cell lines sensitized them to ionizing radiation again. Furthermore, we found miR-214 effectively promoted tumor radioresistance in xenograft animal experiment. Western blotting and quantitative real-time PCR demonstrated that miR-214 negatively regulated PTEN in radioresistance ovarian cancer cell lines and ovarian cancer tissues. Taken together, our data conclude that miR-214 contributes to radioresistance of ovarian cancer by directly targeting PTEN.

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Cell proliferation of human ovarian cancer is regulated by the opioid growth factor-opioid growth factor receptor axis

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00075.2009 ◽

2009 ◽

Vol 296 (6) ◽

pp. R1716-R1725 ◽

Cited By ~ 44

Author(s):

Renee N. Donahue ◽

Patricia J. McLaughlin ◽

Ian S. Zagon

Keyword(s):

Ovarian Cancer ◽

Cell Proliferation ◽

Growth Factor ◽

Cell Lines ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Cancer Cell Lines ◽

Human Ovarian Cancer ◽

Opioid Growth Factor ◽

Ovarian Cancer Cell Lines

Ovarian cancer is the leading cause of death from gynecological malignancies. Understanding the biology of these tumors, as well as treatment modalities, has been challenging. The opioid growth factor (OGF; [Met5]-enkephalin) and the OGF receptor (OGFr) form an endogenous growth-regulating pathway in homeostasis and neoplasia. In this investigation, we examined the relationship of the OGF-OGFr axis to ovarian cancer, and defined its presence, function, and mechanisms. Using OVCAR-3 and SKOV-3 ovarian cancer cell lines, we found that OGF and OGFr were present and functional. Exogenous OGF was observed to have a dose-dependent, serum-independent, reversible, and receptor-mediated inhibitory action on cell proliferation that was dependent on RNA and protein synthesis. The repressive effect of OGF on cell proliferation also was observed in SW626, CAOV-3, and HEY ovarian cancer cell lines. Endogenous OGF was found to be constitutively produced and tonically active on cell replicative activities, with neutralization of this peptide accelerating cell proliferation. Silencing of OGFr using siRNA technology stimulated cell replication, documenting its integral role. The mechanism of OGF-OGFr action on DNA synthesis was related to the cyclin-dependent kinase inhibitory pathway because knockdown of p16 or p21 in OVCAR-3 cells, and p21 in SKOV-3 cells, eliminated OGF's inhibitory effect on growth. These data are the first to report that the OGF-OGFr system is a native biological regulator of cell proliferation in human ovarian cancer. This information will be important in designing treatment strategies for this deadly disease.

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

Acta Endocrinologica ◽

10.1530/eje.0.1420665 ◽

2000 ◽

pp. 665-670 ◽

Cited By ~ 30

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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Tumour-suppressor microRNAs regulate ovarian cancer cell physical properties and invasive behaviour

Open Biology ◽

10.1098/rsob.160275 ◽

2016 ◽

Vol 6 (11) ◽

pp. 160275 ◽

Cited By ~ 13

Author(s):

Clara K. Chan ◽

Yinghong Pan ◽

Kendra Nyberg ◽

Marco A. Marra ◽

Emilia L. Lim ◽

...

Keyword(s):

Ovarian Cancer ◽

Physical Properties ◽

Cancer Cells ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Single Cells ◽

Tumour Suppressor ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

The Impact

The activities of pathways that regulate malignant transformation can be influenced by microRNAs (miRs). Recently, we showed that increased expression of five tumour-suppressor miRs, miR-508-3p, miR-508-5p, miR-509-3p, miR-509-5p and miR-130b-3p, correlate with improved clinical outcomes in human ovarian cancer patients, and that miR-509-3p attenuates invasion of ovarian cancer cell lines. Here, we investigate the mechanism underlying this reduced invasive potential by assessing the impact of these five miRs on the physical properties of cells. Human ovarian cancer cells (HEYA8, OVCAR8) that are transfected with miR mimics representing these five miRs exhibit decreased invasion through collagen matrices, increased cell size and reduced deformability as measured by microfiltration and microfluidic assays. To understand the molecular basis of altered invasion and deformability induced by these miRs, we use predicted and validated mRNA targets that encode structural and signalling proteins that regulate cell mechanical properties. Combined with analysis of gene transcripts by real-time PCR and image analysis of F-actin in single cells, our results suggest that these tumour-suppressor miRs may alter cell physical properties by regulating the actin cytoskeleton. Our findings provide biophysical insights into how tumour-suppressor miRs can regulate the invasive behaviour of ovarian cancer cells, and identify potential therapeutic targets that may be implicated in ovarian cancer progression.

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Gedunin, a Novel Natural Substance, Inhibits Ovarian Cancer Cell Proliferation

International Journal of Gynecological Cancer ◽

10.1111/igc.0b013e3181a83135 ◽

2009 ◽

Vol 19 (9) ◽

pp. 1564-1569 ◽

Cited By ~ 39

Author(s):

Siddharth G. Kamath ◽

Ning Chen ◽

Yin Xiong ◽

Robert Wenham ◽

Sachin Apte ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Proliferation ◽

Cell Lines ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Cancer Cell Lines ◽

Ovarian Cancer Cells ◽

Expression Data ◽

Ovarian Cancer Cell Lines

The discovery of more active therapeutic compounds is essential if the outcome for patients with advanced-stage epithelial ovarian cancer is to be improved. Gedunin, an extract of the neem tree, has been used as a natural remedy for centuries in Asia. Recently, gedunin has been shown to have potential in vitro antineoplastic properties; however, its effect on ovarian cancer cells is unknown. We evaluated the in vitro effect of gedunin on SKOV3, OVCAR4, and OVCAR8 ovarian cancer cell lines proliferation, alone and in the presence of cisplatin. Furthermore, we analyzed in vitro gedunin sensitivity data, integrated with genome-wide expression data from 54 cancer cell lines in an effort to identify genes and molecular pathways that underlie the mechanism of gedunin action. In vitro treatment of ovarian cancer cell lines with gedunin alone produced up to an 80% decrease in cell proliferation (P < 0.01) and, combining gedunin with cisplatin, demonstrated up to a 47% (P < 0.01) decrease in cell proliferation compared with cisplatin treatment alone. Bioinformatic analysis of integrated gedunin sensitivity and gene expression data identified 52 genes to be associated with gedunin sensitivity. These genes are involved in molecular functions related to cell cycle control, carcinogenesis, lipid metabolism, and molecular transportation. We conclude that gedunin has in vitro activity against ovarian cancer cells and, further, may enhance the antiproliferative effect of cisplatin. The molecular determinants of in vitro gedunin response are complex and may include modulation of cell survival and apoptosis pathways.

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Ethanol Extracts of Solanum lyratum Thunb Regulate Ovarian Cancer Cell Proliferation, Apoptosis, and Epithelial-to-Mesenchymal Transition (EMT) via the ROS-Mediated p53 Pathway

Journal of Immunology Research ◽

10.1155/2021/5569354 ◽

2021 ◽

Vol 2021 ◽

pp. 1-16

Author(s):

Chen Zhang ◽

Zheming Li ◽

Jie Wang ◽

Xuelu Jiang ◽

Mengting Xia ◽

...

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Cell Proliferation ◽

Western Blot ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Ovarian Cancer Cells ◽

Cancer Cell Proliferation ◽

Anticancer Effects ◽

Skov3 Cells

Ovarian cancer is a type of common gynecological tumors with high incidence and poor survival. The anticancer effects of the traditional Chinese medicine Solanum lyratum Thunb (SLT) have been intensively investigated in various cancers but in ovarian cancer is rare. The current study is aimed at investigating the effect of SLT on ovarian cancer cells. Lactate dehydrogenase (LDH) and MTT assays indicated that SLT concentrations of 0.25 and 0.5 μg/mL were not cytotoxic and had significant inhibitory effects on the cell viabilities of A2780 and SKOV3 cells, hence were used for subsequent experiments. Flow cytometric and western blot analysis revealed that SLT effectively suppressed ovarian cancer cell proliferation via inducing cell cycle arrest and increasing apoptosis. Cell cycle and apoptosis-related protein expressions were also regulated in SLT-treated cells. Moreover, DCFH-DA and western blot assays demonstrated that SLT enhanced ROS accumulation and subsequently activated the p53 signaling pathway. However, SLT-regulated ovarian cancer cell proliferation, apoptosis, migration, invasion, and EMT were significantly reversed by an ROS inhibitor (NAC, N-acetyl-L-cysteine). Furthermore, A2780 and SKOV3 cells cocultured with M0 macrophages showed that SLT activated the polarization of M0 macrophages to M1 macrophages and inhibited the polarization to M2 macrophages, with the increased percentage of CD86+ cells and decreased percentage of CD206+ cells were detected. In summary, this study illustrated the anticancer effects of SLT on ovarian cancer cells, suggesting that SLT may have the potential to provide basic evidence for the discovery of antiovarian cancer agents.

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CC Chemokine Ligand 7 Derived from Cancer-Stimulated Macrophages Promotes Ovarian Cancer Cell Invasion

Cancers ◽

10.3390/cancers13112745 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2745

Author(s):

Miran Jeong ◽

Yi-Yue Wang ◽

Ju-Yeon Choi ◽

Myong-Cheol Lim ◽

Jung-Hye Choi

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Cell Invasion ◽

Ovarian Cancer Cell ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Cancer Cell Invasion ◽

Cc Chemokine ◽

Chemokine Ligand

In the tumor microenvironment, macrophages have been suggested to be stimulated by tumor cells, becoming tumor-associated macrophages that promote cancer development and progression. We examined the effect of these macrophages on human ovarian cancer cell invasion and found that conditioned medium of macrophages stimulated by ovarian cancer cells (OC-MQs) significantly increased cell invasion. CC chemokine ligand 7 (CCL7) expression and production were significantly higher in OC-MQs than in the control macrophages. Peritoneal macrophages from patients with ovarian cancer showed higher CCL7 expression levels than those from healthy controls. Inhibition of CCL7 using siRNA and neutralizing antibodies reduced the OC-MQ-CM-induced ovarian cancer cell invasion. CC chemokine receptor 3 (CCR3) was highly expressed in human ovarian cancer cells, and a specific inhibitor of this receptor reduced the OC-MQ-CM-induced invasion. Specific signaling and transcription factors were associated with enhanced CCL7 expression in OC-MQs. CCL7-induced invasion required the expression of matrix metalloproteinase 9 via activation of extracellular signal-related kinase signaling in human ovarian cancer cells. These data suggest that tumor-associated macrophages can affect human ovarian cancer metastasis via the CCL7/CCR3 axis.

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Lysine-specific demethylase 1 (LSD1) promotes ovarian cancer cell progression by Forkhead box O 3a (FOXO3a) inhibition

Materials Express ◽

10.1166/mex.2020.1674 ◽

2020 ◽

Vol 10 (4) ◽

pp. 594-602 ◽

Cited By ~ 2

Author(s):

Li Liu ◽

Fuxing Hao ◽

Anping Wang ◽

Xiaolan Chen ◽

Bin Zhang ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Proliferation ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Soft Agar ◽

Ovarian Cancer Cells ◽

Cancer Cell Growth ◽

Forkhead Box ◽

Lysine Specific Demethylase ◽

Cell Progression

Recently, LSD1 is considered as a possible therapeutic mark for ovarian epithelial cancer (OEC). Though, the underlying molecular mechanism by which LSD1 endorses the oncogenesis of OEC has not been fully understood. Here, we revealed that overexpression of LSD1 downregulated Forkhead box O 3a (FOXO3a), while knockdown or pharmacological inhibition of LSD1 upregulated FOXO3a expression. Specifically, LSD1 interacted with demethylated FOXO3a. The LSD1-demethylated FOXO3a degraded via an ubiquitin-proteasome pathway. Biologically, LSD1 destabilized FOXO3a to abrogate its functions in the suppression of soft agar colony and cell proliferation formation in HO8910 ovarian cancer cells. Knockdown of FOXO3a rescued the restricted cell proliferation by LSD1 downregulation. As a whole, our study clarifies a way in ovarian cancer cell growth through the negative regulation of FOXO3a by LSD1.

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