Curcumin derivative ST09 modulates the miR-199a-5p/DDR1 axis and regulates proliferation and migration in ovarian cancer cells

AbstractOvarian cancers are among the fatal malignancies affecting women globally, mainly due to their metastatic and chemoresistant nature. In this study, we report a potent curcumin derivative ST09 effective against ovarian cancers. Prior in-vitro studies with ST09 drug showed cytotoxicity in tumorigenic cells compared to normal cells and in-vivo, significant tumor reduction was observed with least systemic toxicity. ST09 induced cytotoxicity in the ovarian cancer cells triggering mitochondria-mediated intrinsic apoptotic pathway. Delving deeper to understand the underlying molecular mechanisms involved in ovarian cancer pathogenesis, we identified an inverse correlation of miR-199a-5p with DDR1, a collagen receptor with receptor tyrosine kinase activity. The ST09 treatment in ovarian cancer cell lines resulted in the deregulation of the miR-199a-5p/DDR1 axis, conferring tumor-suppressive functions. We established DDR1 to be a direct target of miR-199a-5p and that ST09-induced DDR1 loss in these ovarian cancer cells resulted in the inactivation of its downstream MMP activation, migration, EMT, and prosurvival NF-κB pathway. Overall this study demonstrates ST09, a potent drug candidate for ovarian cancer treatment which exhibits anti-invasive and migrastatic properties.

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Plasma cells shape the mesenchymal identity of ovarian cancers through transfer of exosome-derived microRNAs

Science Advances ◽

10.1126/sciadv.abb0737 ◽

2021 ◽

Vol 7 (9) ◽

pp. eabb0737

Author(s):

Zhengnan Yang ◽

Wei Wang ◽

Linjie Zhao ◽

Xin Wang ◽

Ryan C. Gimple ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Plasma Cell ◽

Plasma Cells ◽

Ovarian Cancer Cells ◽

Mesenchymal Phenotype ◽

Ovarian Cancers ◽

Novel Approach

Ovarian cancer represents a highly lethal disease that poses a substantial burden for females, with four main molecular subtypes carrying distinct clinical outcomes. Here, we demonstrated that plasma cells, a subset of antibody-producing B cells, were enriched in the mesenchymal subtype of high-grade serous ovarian cancers (HGSCs). Plasma cell abundance correlated with the density of mesenchymal cells in clinical specimens of HGSCs. Coculture of nonmesenchymal ovarian cancer cells and plasma cells induced a mesenchymal phenotype of tumor cells in vitro and in vivo. Phenotypic switch was mediated by the transfer of plasma cell–derived exosomes containing miR-330-3p into nonmesenchymal ovarian cancer cells. Exosome-derived miR-330-3p increased expression of junctional adhesion molecule B in a noncanonical fashion. Depletion of plasma cells by bortezomib reversed the mesenchymal characteristics of ovarian cancer and inhibited in vivo tumor growth. Collectively, our work suggests targeting plasma cells may be a novel approach for ovarian cancer therapy.

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Matrine inhibits the development and progression of ovarian cancer by repressing cancer associated phosphorylation signaling pathways

Cell Death and Disease ◽

10.1038/s41419-019-2013-3 ◽

2019 ◽

Vol 10 (10) ◽

Cited By ~ 3

Author(s):

Xi Zhang ◽

Guoqing Hou ◽

Andong Liu ◽

Hui Xu ◽

Yang Guan ◽

...

Keyword(s):

Ovarian Cancer ◽

Side Effects ◽

Cancer Cells ◽

Signaling Pathways ◽

Molecular Mechanisms ◽

Chemotherapy Resistance ◽

Treatment Strategies ◽

Ovarian Cancer Cells

Abstract Ovarian cancer remains the most lethal gynecologic malignancy with late detection and acquired chemoresistance. Advanced understanding of the pathophysiology and novel treatment strategies are urgently required. A growing body of proteomic investigations suggest that phosphorylation has a pivotal role in the regulation of ovarian cancer associated signaling pathways. Matrine has been extensively studied for its potent anti-tumor activities. However, its effect on ovarian cancer cells and underlying molecular mechanisms remain unclear. Herein we showed that matrine treatment inhibited the development and progression of ovarian cancer cells by regulating proliferation, apoptosis, autophagy, invasion and angiogenesis. Matrine treatment retarded the cancer associated signaling transduction by decreasing the phosphorylation levels of ERK1/2, MEK1/2, PI3K, Akt, mTOR, FAK, RhoA, VEGFR2, and Tie2 in vitro and in vivo. Moreover, matrine showed excellent antitumor effect on chemoresistant ovarian cancer cells. No obvious toxic side effects were observed in matrine-administrated mice. As the natural agent, matrine has the potential to be the targeting drug against ovarian cancer cells with the advantages of overcoming the chemotherapy resistance and decreasing the toxic side effects.

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Bromodomain-containing protein 4 regulates interleukin-34 expression in mouse ovarian cancer cells

Inflammation and Regeneration ◽

10.1186/s41232-020-00129-4 ◽

2020 ◽

Vol 40 (1) ◽

Author(s):

Nanumi Han ◽

Delnur Anwar ◽

Naoki Hama ◽

Takuto Kobayashi ◽

Hidefumi Suzuki ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Growth ◽

Tumor Progression ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Ovarian Cancer Cell Line ◽

Cancer Cell Line ◽

Ovarian Cancer Cells ◽

Mouse Tumor

Abstract Background Interleukin (IL)-34 acts as an alternative ligand for the colony-stimulating factor-1 receptor and controls the biology of myeloid cells, including survival, proliferation, and differentiation. IL-34 has been reported to be expressed in cancer cells and to promote tumor progression and metastasis of certain cancers via the promotion of angiogenesis and immunosuppressive macrophage differentiation. We have shown in our previous reports that targeting IL-34 in chemo-resistant tumors in vitro resulted in a remarkable inhibition of tumor growth. Also, we reported poor prognosis in patients with IL-34-expressing tumor. Therefore, blocking of IL-34 is considered as a promising therapeutic strategy to suppress tumor progression. However, the molecular mechanisms that control IL-34 production are still largely unknown. Methods IL-34 producing ovarian cancer cell line HM-1 was treated by bromodomain and extra terminal inhibitor JQ1. The mRNA and protein expression of IL-34 was evaluated after JQ1 treatment. Chromatin immunoprecipitation was performed to confirm the involvement of bromodomain-containing protein 4 (Brd4) in the regulation of the Il34 gene. Anti-tumor effect of JQ1 was evaluated in mouse tumor model. Results We identified Brd4 as one of the critical molecules that regulate Il34 expression in cancer cells. Consistent with this, we found that JQ1 is capable of efficiently suppressing the recruitment of Brd4 to the promotor region of Il34 gene. Additionally, JQ1 treatment of mice bearing IL-34-producing tumor inhibited the tumor growth along with decreasing Il34 expression in the tumor. Conclusion The results unveiled for the first time the responsible molecule Brd4 that regulates Il34 expression in cancer cells and suggested its possibility as a treatment target.

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Metformin inhibits the growth of ovarian cancer cells by promoting the Parkin-induced p53 ubiquitination

Bioscience Reports ◽

10.1042/bsr20200679 ◽

2020 ◽

Cited By ~ 1

Author(s):

Xiaojia Min ◽

Tingting Zhang ◽

Ying Lin ◽

Bo Wang ◽

Kean Zhu

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Ovarian Cancer Cells ◽

Related Factors ◽

P53 Signaling ◽

P53 Signaling Pathway ◽

Resistant Cells

Ovarian cancer is the most lethal diseases among women. The chemo-resistance has been a big challenge for the cancer treatment. It has been reported that metformin may inhibit ovarian cancer and is able to impede the development of drug resistance, but the molecular mechanisms remain elusive. In this study, we explored the molecular roles of metformin in Parkin expression and p53 ubiquitination in chemo-resistant ovarian cancer cells. Firstly, ovarian cancer and chemo-resistant ovarian cancer cells were selected for determining the expression of Parkin, p53, and p53 signaling pathway-related factors. Then the cell proliferation and viability after loss- and gain-of-function assays were measured. Besides, immunoprecipitation (IP) was used to determine the interactions between Parkin and p53, and the ubiquitination level of p53 was measured using in vitro ubiquitination assay. Finally, the degradation of p53 proteasome regulated by Parkin was monitored using the MG132 proteasome inhibitor. We found that metformin significantly inhibited the growth of ovarian cancer parental cells and chemo-resistant cells, and metformin promoted Parkin expression in chemo-resistant cells. Further, up-regulated Parkin expression promoted the ubiquitination and degradation of p53, and metformin inhibited the expression of p53 to suppress the proliferation of chemo-resistant ovarian cancer cells. Mechanistically, metformin could inhibit the growth of ovarian cancer cells by promoting the Parkin-induced p53 ubiquitination. Altogether, our study demonstrated an inhibitory role of metformin in the growth of chemo-resistant cancer cells through promoting the Parkin-induced p53 ubiquitination, which provides a novel mechanism of metformin for treating ovarian cancer.

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Puerarin induces platinum-resistant epithelial ovarian cancer cell apoptosis by targeting SIRT1

Journal of International Medical Research ◽

10.1177/03000605211040762 ◽

2021 ◽

Vol 49 (9) ◽

pp. 030006052110407

Author(s):

Jianxiu Duan ◽

Mingyuan Yin ◽

Yaqin Shao ◽

Jiao Zheng ◽

Shengdan Nie

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Sirtuin 1 ◽

Nuclear Accumulation ◽

Ovarian Cancer Cells ◽

Platinum Resistant

Objective Previous investigations indicated the anticancer activity of puerarin. The current study aimed to evaluate the effect and molecular mechanisms of puerarin in chemotherapy-resistant ovarian cancer cells. Methods We examined the effects of puerarin in platinum-resistant epithelial ovarian cancer cells in vitro and in vivo. We also analyzed the molecular mechanism underlying Wnt/β-catenin inhibition and sirtuin 1 (SIRT1) regulation following puerarin treatment. Results Our study demonstrated that puerarin effectively inhibited cell growth in vitro and in vivo by increasing apoptosis in ovarian cancer cells. More importantly, puerarin sensitized cisplatin-resistant ovarian cancer cells to chemotherapy. Puerarin treatment decreased SIRT1 expression, which attenuated the nuclear accumulation of β-catenin to inhibit Wnt/β-catenin signaling. In addition, SIRT1 overexpression diminished the effects of puerarin treatment on cisplatin-resistant ovarian cancer cells. Further analysis supported SIRT1/β-catenin expression as a candidate biomarker for the disease progression of epithelial ovarian cancer. Conclusions Puerarin increased the apoptosis of platinum-resistant ovarian cancer cells. The mechanism is partly related to the downregulation of SIRT1 and subsequent inhibition of Wnt/β-catenin signaling.

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LINC00494 Promotes Ovarian Cancer Development and Progression by Modulating NFκB1 and FBXO32

Frontiers in Oncology ◽

10.3389/fonc.2020.541410 ◽

2021 ◽

Vol 10 ◽

Author(s):

Yang Shu ◽

He Zhang ◽

Jinqiu Li ◽

Yanhong Shan

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Xenograft Model ◽

Luciferase Reporter ◽

Ovarian Cancer Cells ◽

Cancer Pathogenesis ◽

Potential Interactions

BackgroundOvarian cancer represents one of the most frequent gynecological cancers and is significant cause of death for women around the world. Long non-coding RNAs (lncRNAs) are recognized as critical governors of gene expression during carcinogenesis, but their effects on the occurrence and development of ovarian cancer require further investigation. In this report, we characterized LINC00494 as a novel oncogenic lncRNA in ovarian cancer.MethodsBioinformatics analysis predicted potential interactions among LINC00494, NFκB1, and FBXO32 in ovarian cancer, which were tested by dual-luciferase reporter assay, RNA pull-down, RIP, and ChIP assay. Cancer cells were transfected with relevant treated plasmids, followed by scratch and Transwell assays. The treated cells were injected into nude mice to establish a xenograft model for testing effects of LINC00494 and its target gene in vivo.ResultsLINC00494 and NFκB1 were highly expressed whereas FBXO32 had low expression in ovarian cancer cells and tissues. LINC00494 was found to bind NFκB1 and increase its activity, while NFκB1 was enriched at the FBXO32 promoter region, where it acted to reduce FBXO32 transcription. Overexpression of LINC00494 elevated NFκB1 expression and enhanced cell migration, invasion and tumorigenesis, but additional overexpression of FBXO32 interfered with the tumorgenicity of ovarian cancer cells in vitro and in vivo.ConclusionOur work demonstrated that LINC00494 promoted ovarian cancer progression by modulating FBXO32 via binding with the transcription factor NFκB1. These results provided new insight into the mechanism of ovarian cancer pathogenesis and suggested new therapeutic targets.

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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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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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