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

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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METTL3 promotes the initiation and metastasis of ovarian cancer by inhibiting CCNG2 expression via promoting the maturation of pri-microRNA-1246

Cell Death Discovery ◽

10.1038/s41420-021-00600-2 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Xuehan Bi ◽

Xiao Lv ◽

Dajiang Liu ◽

Hongtao Guo ◽

Guang Yao ◽

...

Keyword(s):

Ovarian Cancer ◽

Molecular Mechanisms ◽

High Expression ◽

Ovarian Cancer Cells ◽

Inadequate Knowledge ◽

And Migration ◽

Cancer Tissues

AbstractOvarian cancer is a common gynecological malignant tumor with a high mortality rate and poor prognosis. There is inadequate knowledge of the molecular mechanisms underlying ovarian cancer. We examined the expression of methyltransferase-like 3 (METTL3) in tumor specimens using RT-qPCR, immunohistochemistry, and Western blot analysis, and tested the methylation of METTL3 by MSP. Levels of METTL3, miR-1246, pri-miR-1246 and CCNG2 were then analyzed and their effects on cell biological processes were also investigated, using in vivo assay to validate the in vitro findings. METTL3 showed hypomethylation and high expression in ovarian cancer tissues and cells. Hypomethylation of METTL3 was pronounced in ovarian cancer samples, which was negatively associated with patient survival. Decreased METTL3 inhibited the proliferation and migration of ovarian cancer cells and promoted apoptosis, while METTL3 overexpression exerted opposite effects. Mechanistically, METTL3 aggravated ovarian cancer by targeting miR-1246, while miR-1246 targeted and inhibited CCNG2 expression. High expression of METTL3 downregulated CCNG2, promoted the metabolism and growth of transplanted tumors in nude mice, and inhibited apoptosis. The current study highlights the promoting role of METTL3 in the development of ovarian cancer, and presents new targets for its treatment.

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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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Role of tissue-factor bearing extracellular vesicles released from ovarian cancer cells in platelet aggregation in vitro and venous thrombosis in mice

Thrombosis Update ◽

10.1016/j.tru.2020.100020 ◽

2021 ◽

Vol 2 ◽

pp. 100020

Author(s):

Tomoyuki Sasano ◽

Min Soon Cho ◽

Cristian Rodriguez-Aguayo ◽

Emine Bayraktar ◽

Mana Taki ◽

...

Keyword(s):

Ovarian Cancer ◽

Platelet Aggregation ◽

Venous Thrombosis ◽

Cancer Cells ◽

Tissue Factor ◽

Extracellular Vesicles ◽

Ovarian Cancer Cells

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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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Possible role of FLICE-like inhibitory protein (FLIP) in chemoresistant ovarian cancer cells in vitro

Oncogene ◽

10.1038/sj.onc.1207925 ◽

2004 ◽

Vol 23 (42) ◽

pp. 6997-7004 ◽

Cited By ~ 89

Author(s):

Mohammad R Abedini ◽

Qing Qiu ◽

Xiaojuan Yan ◽

Benjamin K Tsang

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Ovarian Cancer Cells ◽

Inhibitory Protein ◽

Chemoresistant Ovarian Cancer

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Esomeprazole improves the acidic microenvironment of epithelial ovarian cancer by inhibiting the expression of VATPase

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v19i8.3 ◽

2020 ◽

Vol 19 (8) ◽

pp. 1585-1590

Author(s):

Yasong Chi ◽

Ruiqin Yue ◽

Yanru Lv ◽

Wei Liao ◽

Ruchang Yin

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Cancer Cells ◽

Ph Value ◽

Ovarian Cancer Cells ◽

Control Group ◽

Acidic Microenvironment ◽

Paclitaxel Group ◽

Resistant Cells

Purpose: To determine the effect of esomeprazole on apoptosis of ovarian cancer cells and their sensitivity to paclitaxel, and the underlying mechanism.Methods: Human ovarian paclitaxel-resistant cancer cells were cultured in vitro, and treated with esomeprazole at doses of 50, 100 and 250 mol/L. Cell proliferation was determined using MTT assay. Paclitaxel-resistant cells were divided into control group, esomeprazole group, paclitaxel group, and esomeprazole + taxol group. Western blot was employed for the assay of protein levels of bcl-2, Bcl-xl, P-gp and V-ATPase, while BCECF-AM method was employed to determine changes in intracellular pH.Results: Esomeprazole significantly inhibited the proliferation of paclitaxel-resistant cells in a dosedependent manner. The half-maximal inhibitory concentration (IC50) value of esomeprazole + paclitaxel was significantly low, when compared with those of the other treatments (p < 0.05). Apoptosis was significantly higher in esomeprazole + paclitaxel group than in any other treatment group (p < 0.05). The expressions of Bcl-2 and P-gp in esomeprazole + paclitaxel group decreased significantly, relative to the corresponding values for other groups, while protein expression of bcl-xl was markedly increased. The intracellular pH value of esomeprazole + paclitaxel group was significantly lower than those for other treatment groups (p < 0.05).Conclusion: Esomeprazole improves the acidic microenvironment of epithelial ovarian cancer by inhibiting the expression of V-ATPase, and restores the sensitivity of ovarian cancer cells to paclitaxel by inhibiting their proliferation and apoptosis. This revelation may explain patients’ resistance topaclitaxel. Keywords: Esomeprazole, V-ATPase, Apoptosis, Ovarian cancer, Taxol, Sensitivity

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Mechanism of resistin-induced enhancement of proliferation and migration of ovarian cancer cells

Archives of Medical Science ◽

10.5114/aoms.2020.100652 ◽

2020 ◽

Author(s):

Li Pang ◽

Xian-li Li

Keyword(s):

Ovarian Cancer ◽

Wound Healing ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Ovarian Cancer Cells ◽

Dependent Manner ◽

Ovarian Epithelial Carcinoma ◽

And Migration ◽

Proliferation And Migration

IntroductionResistin, a novel hormone secreted by human adipocytes and mononuclear cells, is associated with obesity, insulin resistance, and inflammation. Recent studies showed that resistin plays a key role in ovarian cancer cells. In this study, we investigated the potential of resistin to regulate the proliferation and migration of ovarian cancer cells.Material and methodsA series of in vitro functional experiments were carried out to elucidate the role of resistin in ovarian cancer progression and the molecular mechanisms underlying its role.ResultsResistin enhanced the proliferation of human ovarian epithelial carcinoma cells (HO-8910) in a time- and dose-dependent manner (30–100 ng/ml). Furthermore, HO-8910 cells cultured in adipocyte-conditioned medium showed dramatically increased rates of proliferation. Resistin knockout during adipocyte culture attenuated the proliferation of HO-8910 cells treated with adipocyte-conditioned media, indicating that resistin may promote HO-8910 cell proliferation via the mechanistic target of a rapamycin (mTOR)-mediated signaling pathway. Resistin (30–100 ng/ml) also enhanced wound-healing rates in a time- and concentration-dependent manner. Co-culturing HO-8910 cells with adipocytes also increased the wound-healing rates. Resistin expression was inhibited by miR-124-1 transcriptional activity, and resistin-mediated HO-8910 cell migration was also regulated by miR-124-1. Furthermore, we also confirmed the role of resistin in promoting tumor growth in vivo.ConclusionsThese findings suggest that resistin may serve as an effective therapeutic target for ovarian epithelial carcinoma, especially in patients who are obese.

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

Scientific Reports ◽

10.1038/s41598-021-02454-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Febina Ravindran ◽

Jinsha Koroth ◽

Meghana Manjunath ◽

Suchitra Narayan ◽

Bibha Choudhary

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Drug Candidate ◽

Ovarian Cancer Cells ◽

Apoptotic Pathway ◽

Cancer Pathogenesis ◽

Ovarian Cancers ◽

Curcumin Derivative

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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