Effects of celastrol on enhancing apoptosis of ovarian cancer cells via the downregulation of microRNA-21 and the suppression of the PI3K/Akt-NF-κB signaling pathway in an in vitro model of ovarian carcinoma

Abstract Background: Wnt-inducible signaling pathway protein 2 (WISP2) is a wnt1-induced signaling pathway protein 2. Although studies indicate that WISP2 may promote the development of various tumors, its role in ovarian cancer remains unclear. The objective of the current study was to analyze the effects of WISP2 on the proliferation and migration of ovarian cancer cells in vitro and in vivo.Results: Immunohistochemistry and western blotting indicated that WISP2 was highly expressed in various ovarian cancer tissues and cell lines，but weakly expressed in normal ovary tissue. WISP2 deletion inhibited cell growth, clone formation, and migration of ovarian cancer cells while promoting cell apoptosis and affecting the cell cycle. This growth inhibitory effect caused by WISP2 loss is due to the inhibition of phosphorylated extracellular signal-related kinase (p-ERK)1/2, as well as CCAAT/enhancer-binding protein α (CEBPα) and CEPBβ. In addition, WISP2 deletion also activated the Yes-associated protein (YAP).Conclusion: WISP2 deletion inhibits ovarian cancer cell proliferation by affecting ERK signaling pathways.

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Zinc transporter SLC39A13/ZIP13 facilitates the metastasis of human ovarian cancer cells via activating Src/FAK signaling pathway

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01999-3 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Xinxin Cheng ◽

Jie Wang ◽

Chunling Liu ◽

Tianduo Jiang ◽

Ningzhi Yang ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Clinical Outcomes ◽

Zinc Transporter ◽

Zinc Transporters ◽

Ovarian Cancer Cells ◽

Rapid Progression

Abstract Background Zinc transporters have been found to be associated with the pathogenesis of numerous human diseases including cancer. As the most lethal gynecologic malignancy, ovarian cancer is characterized by rapid progression and widespread metastases. However, the function and underlying mechanism of zinc transporters in ovarian cancer metastasis remain unclear. Methods The relationship between zinc transporter gene expressions and clinical outcomes of ovarian cancer was assessed with the online database Kaplan-Meier plotter (http://kmplot.com/analysis/). Immunohistochemistry was performed to investigate the prognostic importance of ZIP13. The expression of ZIP13 in ovarian cancer cell lines was depleted to explore its effect on proliferation, adhesion, migration, and invasion both in vitro and in vivo assays. RNA-Seq, quantitative RT-PCR, and western blot analysis were performed to explore ZIP13-regulated downstream target genes. Results The expressions of several zinc transporters were highly associated the clinical outcomes of ovarian cancer patients. Among them, high ZIP13 expression was an independent prognostic factor for poor survival in patients with ovarian cancer. ZIP13 knockout suppressed the malignant phenotypes of ovarian cancer cells both in vitro and in vivo. Further investigation revealed that ZIP13 regulated intracellular zinc distribution and then affected the expressions of genes involved in extracellular matrix organization and cytokine-mediated signaling pathway. This led to the activation of Src/FAK pathway with increased expressions of pro-metastatic genes but decreased expressions of tumor suppressor genes. Conclusions ZIP13 is shown to be a novel driver of metastatic progression by modulating the Src/FAK signaling pathway, which may serve as a promising biomarker for prognostic evaluation and targeted therapy in ovarian cancer.

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TTK inhibition increases cisplatin sensitivity in high-grade serous ovarian carcinoma through the mTOR/autophagy pathway

Cell Death and Disease ◽

10.1038/s41419-021-04429-6 ◽

2021 ◽

Vol 12 (12) ◽

Author(s):

Gonghua Qi ◽

Hanlin Ma ◽

Yingwei Li ◽

Jiali Peng ◽

Jingying Chen ◽

...

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Ovarian Carcinoma ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Spindle Assembly Checkpoint ◽

Ovarian Cancer Cells ◽

High Grade ◽

Cisplatin Sensitivity

AbstractHigh-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy. However, the molecular mechanisms underlying HGSOC development, progression, chemotherapy insensitivity and resistance remain unclear. Two independent GEO datasets, including the gene expression profile of primary ovarian carcinoma and normal controls, were analyzed to identify genes related to HGSOC development and progression. A KEGG pathway analysis of the differentially expressed genes (DEGs) revealed that the cell cycle pathway was the most enriched pathway, among which TTK protein kinase (TTK) was the only gene with a clinical-grade inhibitor that has been investigated in a clinical trial but had not been studied in HGSOC. TTK was also upregulated in cisplatin-resistant ovarian cancer cells from two other datasets. TTK is a regulator of spindle assembly checkpoint signaling, playing an important role in cell cycle control and tumorigenesis in various cancers. However, the function and regulatory mechanism of TTK in HGSOC remain to be determined. In this study, we observed TTK upregulation in patients with HGSOC. High TTK expression was related to a poor prognosis. Genetic and pharmacological inhibition of TTK impeded the proliferation of ovarian cancer cells by disturbing cell cycle progression and increasing apoptosis. TTK silencing increased cisplatin sensitivity by activating the mammalian target of rapamycin (mTOR) complex to further suppress cisplatin-induced autophagy in vitro. In addition, the enhanced sensitivity was partially diminished by rapamycin-mediated inhibition of mTOR in TTK knockdown cells. Furthermore, TTK knockdown increased the toxicity of cisplatin in vivo by decreasing autophagy. These findings suggest that the administration of TTK inhibitors in combination with cisplatin may lead to improved response rates to cisplatin in patients with HGSOC presenting high TTK expression. In summary, our study may provide a theoretical foundation for using the combination therapy of cisplatin and TTK inhibitors as a treatment for HGSOC in the future.

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Cytotoxic effects of disulfiram and synergism with cisplatin on ovarian cancer cells in vitro

10.1055/s-0038-1671352 ◽

2018 ◽

Author(s):

F Guo ◽

Z Yang ◽

J Xu ◽

J Sehouli ◽

AE Albers ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Ovarian Cancer Cells ◽

Cytotoxic Effects

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Propofol inhibits proliferation, migration, invasion and promotes apoptosis by regulating HOST2/JAK2/STAT3 signaling pathway in ovarian cancer cells

Cytotechnology ◽

10.1007/s10616-021-00462-7 ◽

2021 ◽

Vol 73 (2) ◽

pp. 243-252

Author(s):

Xiang Shen ◽

Diaolan Wang ◽

Xu Chen ◽

Jun Peng

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Ovarian Cancer Cells ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway

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Electrochemotherapy with Calcium Chloride and 17β-Estradiol Modulated Viability and Apoptosis Pathway in Human Ovarian Cancer

Pharmaceutics ◽

10.3390/pharmaceutics13010019 ◽

2020 ◽

Vol 13 (1) ◽

pp. 19

Author(s):

Zofia Łapińska ◽

Michał Dębiński ◽

Anna Szewczyk ◽

Anna Choromańska ◽

Julita Kulbacka ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Calcium Chloride ◽

Morphological Changes ◽

Cell Membrane Permeability ◽

Immunocytochemical Staining ◽

Ovarian Cancer Cells ◽

Apoptosis Pathway ◽

17Β Estradiol

Estrogens (Es) play a significant role in the carcinogenesis and progression of ovarian malignancies. Depending on the concentration, Es may have a protective or toxic effect on cells. Moreover, they can directly or indirectly affect the activity of membrane ion channels. In the presented study, we investigated in vitro the effectiveness of the ovarian cancer cells (MDAH-2774) pre-incubation with 17β-estradiol (E2; 10 µM) in the conventional chemotherapy (CT) and electrochemotherapy (ECT) with cisplatin or calcium chloride. We used three different protocols of electroporation including microseconds (µsEP) and nanoseconds (nsEP) range. The cytotoxic effect of the applied treatment was examined by the MTT assay. We used fluorescent staining and holotomographic imaging to observe morphological changes. The immunocytochemical staining evaluated the expression of the caspase-12. The electroporation process’s effectiveness was analyzed by a flow cytometer using the Yo-Pro™-1 dye absorption assay. We found that pre-incubation of ovarian cancer cells with 17β-estradiol may effectively enhance the chemo- and electrochemotherapy with cisplatin and calcium chloride. At the same time, estradiol reduced the effectiveness of electroporation, which may indicate that the mechanism of increasing the effectiveness of ECT by E2 is not related to the change of cell membrane permeability.

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Genetic Perturbation of Pyruvate Dehydrogenase Kinase 1 Modulates Growth, Angiogenesis and Metabolic Pathways in Ovarian Cancer Xenografts

Cells ◽

10.3390/cells10020325 ◽

2021 ◽

Vol 10 (2) ◽

pp. 325

Author(s):

Carolina Venturoli ◽

Ilaria Piga ◽

Matteo Curtarello ◽

Martina Verza ◽

Giovanni Esposito ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Pyruvate Dehydrogenase ◽

Metabolic Pathways ◽

Negative Impact ◽

Digital Pathology ◽

Pyruvate Dehydrogenase Kinase ◽

Ovarian Cancer Cells ◽

Pyruvate Dehydrogenase Kinase 1

Pyruvate dehydrogenase kinase 1 (PDK1) blockade triggers are well characterized in vitro metabolic alterations in cancer cells, including reduced glycolysis and increased glucose oxidation. Here, by gene expression profiling and digital pathology-mediated quantification of in situ markers in tumors, we investigated effects of PDK1 silencing on growth, angiogenesis and metabolic features of tumor xenografts formed by highly glycolytic OC316 and OVCAR3 ovarian cancer cells. Notably, at variance with the moderate antiproliferative effects observed in vitro, we found a dramatic negative impact of PDK1 silencing on tumor growth. These findings were associated with reduced angiogenesis and increased necrosis in the OC316 and OVCAR3 tumor models, respectively. Analysis of viable tumor areas uncovered increased proliferation as well as increased apoptosis in PDK1-silenced OVCAR3 tumors. Moreover, RNA profiling disclosed increased glucose catabolic pathways—comprising both oxidative phosphorylation and glycolysis—in PDK1-silenced OVCAR3 tumors, in line with the high mitotic activity detected in the viable rim of these tumors. Altogether, our findings add new evidence in support of a link between tumor metabolism and angiogenesis and remark on the importance of investigating net effects of modulations of metabolic pathways in the context of the tumor microenvironment.

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