IL-6 promotes nuclear translocation of HIF-1α to aggravate chemoresistance of ovarian cancer cells

FEN1 plays critical roles in long patch base excision repair (LP-BER), Okazaki fragment maturation, and rescue of stalled replication forks. In a clinical cohort, FEN1 overexpression is associated with aggressive phenotype and poor progression-free survival after platinum chemotherapy. Pre-clinically, FEN1 is induced upon cisplatin treatment, and nuclear translocation of FEN1 is dependent on physical interaction with importin β. FEN1 depletion, gene inactivation, or inhibition re-sensitizes platinum-resistant ovarian cancer cells to cisplatin. BRCA2 deficient cells exhibited synthetic lethality upon treatment with a FEN1 inhibitor. FEN1 inhibitor-resistant PEO1R cells were generated, and these reactivated BRCA2 and overexpressed the key repair proteins, POLβ and XRCC1. FEN1i treatment was selectively toxic to POLβ deficient but not XRCC1 deficient ovarian cancer cells. High throughput screening of 391,275 compounds identified several FEN1 inhibitor hits that are suitable for further drug development. We conclude that FEN1 is a valid target for ovarian cancer therapy.

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Substrate Stiffness Modulates the Growth, Phenotype, and Chemoresistance of Ovarian Cancer Cells

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.718834 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yali Fan ◽

Quanmei Sun ◽

Xia Li ◽

Jiantao Feng ◽

Zhuo Ao ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Nuclear Translocation ◽

Substrate Stiffness ◽

Ovarian Cancer Cells ◽

Physical Parameters ◽

Chemotherapeutic Drugs ◽

Multidrug Resistance Proteins ◽

Mesenchymal Transition ◽

Growth Phenotype

Mechanical factors in the tumor microenvironment play an important role in response to a variety of cellular activities in cancer cells. Here, we utilized polyacrylamide hydrogels with varying physical parameters simulating tumor and metastatic target tissues to investigate the effect of substrate stiffness on the growth, phenotype, and chemotherapeutic response of ovarian cancer cells (OCCs). We found that increasing the substrate stiffness promoted the proliferation of SKOV-3 cells, an OCC cell line. This proliferation coincided with the nuclear translocation of the oncogene Yes-associated protein. Additionally, we found that substrate softening promoted elements of epithelial-mesenchymal transition (EMT), including mesenchymal cell shape changes, increase in vimentin expression, and decrease in E-cadherin and β-catenin expression. Growing evidence demonstrates that apart from contributing to cancer initiation and progression, EMT can promote chemotherapy resistance in ovarian cancer cells. Furthermore, we evaluated tumor response to standard chemotherapeutic drugs (cisplatin and paclitaxel) and found antiproliferation effects to be directly proportional to the stiffness of the substrate. Nanomechanical studies based on atomic force microscopy (AFM) have revealed that chemosensitivity and chemoresistance are related to cellular mechanical properties. The results of cellular elastic modulus measurements determined by AFM demonstrated that Young’s modulus of SKOV-3 cells grown on soft substrates was less than that of cells grown on stiff substrates. Gene expression analysis of SKOV-3 cells showed that mRNA expression can be greatly affected by substrate stiffness. Finally, immunocytochemistry analyses revealed an increase in multidrug resistance proteins, namely, ATP binding cassette subfamily B member 1 and member 4 (ABCB1 and ABCB4), in the cells grown on the soft gel resulting in resistance to chemotherapeutic drugs. In conclusion, our study may help in identification of effective targets for cancer therapy and improve our understanding of the mechanisms of cancer progression and chemoresistance.

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Non-Phosphorylatable PEA-15 Sensitises SKOV-3 Ovarian Cancer Cells to Cisplatin

Cells ◽

10.3390/cells9020515 ◽

2020 ◽

Vol 9 (2) ◽

pp. 515 ◽

Cited By ~ 1

Author(s):

Shahana Dilruba ◽

Alessia Grondana ◽

Anke C. Schiedel ◽

Naoto T. Ueno ◽

Chandra Bartholomeusz ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Nuclear Translocation ◽

Antioxidant Response ◽

The Cancer Genome Atlas ◽

Favourable Effect ◽

Ovarian Cancer Cells ◽

Related Factor ◽

Potential Candidate ◽

Cisplatin Sensitivity

The efficacy of cisplatin-based chemotherapy in ovarian cancer is often limited by the development of drug resistance. In most ovarian cancer cells, cisplatin activates extracellular signal-regulated kinase1/2 (ERK1/2) signalling. Phosphoprotein enriched in astrocytes (PEA-15) is a ubiquitously expressed protein, capable of sequestering ERK1/2 in the cytoplasm and inhibiting cell proliferation. This and other functions of PEA-15 are regulated by its phosphorylation status. In this study, the relevance of PEA-15 phosphorylation state for cisplatin sensitivity of ovarian carcinoma cells was examined. The results of MTT-assays indicated that overexpression of PEA-15AA (a non-phosphorylatable variant) sensitised SKOV-3 cells to cisplatin. Phosphomimetic PEA-15DD did not affect cell sensitivity to the drug. While PEA-15DD facilitates nuclear translocation of activated ERK1/2, PEA-15AA acts to sequester the kinase in the cytoplasm as shown by Western blot. Microarray data indicated deregulation of thirteen genes in PEA-15AA-transfected cells compared to non-transfected or PEA-15DD-transfected variants. Data derived from The Cancer Genome Atlas (TCGA) showed that the expression of seven of these genes including EGR1 (early growth response protein 1) and FLNA (filamin A) significantly correlated with the therapy outcome in cisplatin-treated cancer patients. Further analysis indicated the relevance of nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signalling for the favourable effect of PEA-15AA on cisplatin sensitivity. The results warrant further evaluation of the PEA-15 phosphorylation status as a potential candidate biomarker of response to cisplatin-based chemotherapy.

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92 Role of ERK nuclear translocation in cisplatin-sensitive and -resistant ovarian cancer cells

European Journal of Cancer ◽

10.1016/s0959-8049(14)70218-7 ◽

2014 ◽

Vol 50 ◽

pp. 34

Author(s):

S. Dilruba ◽

G.V. Kalayda ◽

U. Jaehde

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Nuclear Translocation ◽

Ovarian Cancer Cells

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JNK- and Akt-mediated Puma expression in the apoptosis of cisplatin-resistant ovarian cancer cells

Biochemical Journal ◽

10.1042/bj20111855 ◽

2012 ◽

Vol 444 (2) ◽

pp. 291-301 ◽

Cited By ~ 33

Author(s):

Zhiwei Zhao ◽

Jingjing Wang ◽

Jingsheng Tang ◽

Xinyu Liu ◽

Qian Zhong ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Critical Role ◽

P53 Gene ◽

Dominant Negative ◽

Ovarian Cancer Cells ◽

Puma Expression ◽

Domain 3

BH3 (Bcl-2 homology domain 3)-only proteins have an important role in the cisplatin resistance of cells. However, the effect of BH3-only proteins on cisplatin-resistant ovarian cancer cells has not been thoroughly elucidated. Our results from the present study indicate that Puma plays a critical role in the apoptosis of chemo-resistant ovarian cancer cells treated with BetA (betulinic acid). The reduction of Puma expression inhibits Bax activation and apoptosis. However, p53 gene silencing has little effect on Puma activation. Further experiments demonstrated that Akt-mediated FoxO3a (forkhead box O3a) nuclear translocation and the JNK (c-Jun N-terminal kinase)/c-Jun pathway only partially trigger Puma induction and apoptosis, whereas dominant-negative c-Jun expression with FoxO3a reduction completely inhibits Puma expression and cell death. Furthermore, our results suggest that JNK regulates the Akt/FoxO3a signalling pathway. Therefore the dual effect of JNK can efficiently trigger Puma activation and apoptosis in chemoresistant cells. Taken together, our results demonstrate the role of Puma in BetA-induced apoptosis and the molecular mechanisms of Puma expression regulated by BetA during ovarian cancer cell apoptosis. Our findings suggest that the JNK-potentiated Akt/FoxO3a and JNK-mediated c-Jun pathways co-operatively trigger Puma expression, which determines the threshold for overcoming chemoresistance in ovarian cancer cells.

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Gonadotropin-Releasing Hormone-II Increases Membrane Type I Metalloproteinase Production via β-Catenin Signaling in Ovarian Cancer Cells

Endocrinology ◽

10.1210/en.2010-0942 ◽

2011 ◽

Vol 152 (3) ◽

pp. 764-772 ◽

Cited By ~ 14

Author(s):

Song Ling Poon ◽

Man-Tat Lau ◽

Geoffrey L. Hammond ◽

Peter C. K. Leung

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Cancer Metastasis ◽

Nuclear Translocation ◽

Glycogen Synthase ◽

Gnrh Receptor ◽

Akt Pathway ◽

Ovarian Cancer Cells ◽

Type I ◽

Membrane Type

GnRH-II is produced by ovarian cancer cells and enhances their invasiveness in vitro. In our studies of OVCAR-3 and CaOV-3 ovarian cancer cell lines, GnRH-II treatment induced phosphorylation of Akt and glycogen synthase kinase (GSK)3β, as well as β-catenin accumulation in the nucleus, and the latter was reduced by small interfering RNA (siRNA)-mediated depletion of the GnRH receptor. The phosphatidylinositol 3 kinase (PI3K)/Akt pathway is involved in β-catenin-dependent signaling, and pretreatment of these human ovarian cancer cells with a PI3K/Akt inhibitor, LY294002, attenuated GnRH-II-stimulated phosphorylation of GSK3β and inhibited GnRH-II-induced invasion. It also attenuated GnRH-II induced trans-activation of a β-catenin-dependent reporter gene, most likely because GSK3β phosphorylation promotes translocation of β-catenin to the nucleus. Membrane type I matrix metalloproteinase (MT1-MMP) contributes to tumor progression directly, or by processing the latent MMP-2 zymogen, and is a known target of β-catenin signaling. When OVCAR-3 and CaOV-3 cells were treated with GnRH-II, MT1-MMP levels increased approximately 3-fold, whereas siRNA-mediated depletion of GnRH receptor or pretreatment with LY294002 abrogated this. In addition, lithium chloride, which increases GSK3β phosphorylation and the nuclear translocation of β-catenin, increased MT1-MMP levels in these ovarian cancer cells. By contrast, depletion of β-catenin by siRNA treatment abolished GnRH-II-induced MT1-MMP synthesis and reduced their invasive potential. Furthermore, siRNA-mediated reduction of MT1-MMP levels reduced GnRH-II-induced invasion in ovarian cancer cells. We therefore conclude that GnRH-II stimulates the PI3K/Akt pathway, and the phosphorylation of GSK3β, thereby enhancing the β-catenin-dependent up-regulation of MT1-MMP production, which contributes to ovarian cancer metastasis.

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Akt2 Kinase Suppresses Glyceraldehyde-3-phosphate Dehydrogenase (GAPDH)-mediated Apoptosis in Ovarian Cancer Cells via Phosphorylating GAPDH at Threonine 237 and Decreasing Its Nuclear Translocation

Journal of Biological Chemistry ◽

10.1074/jbc.m111.296905 ◽

2011 ◽

Vol 286 (49) ◽

pp. 42211-42220 ◽

Cited By ~ 59

Author(s):

Qiaojia Huang ◽

Fenghua Lan ◽

Zhiyong Zheng ◽

Feilai Xie ◽

Junyong Han ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Nuclear Translocation ◽

Ovarian Cancer Cells

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ZNF703 promotes tumor progression in ovarian cancer by interacting with HE4 and epigenetically regulating PEA15

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01770-0 ◽

2020 ◽

Vol 39 (1) ◽

Author(s):

Shuang Wang ◽

Caixia Wang ◽

Yuexin Hu ◽

Xiao Li ◽

Shan Jin ◽

...

Keyword(s):

Ovarian Cancer ◽

Transcription Factor ◽

Cancer Cells ◽

Cancer Patients ◽

Nuclear Translocation ◽

Biological Behavior ◽

Luciferase Reporter ◽

Ovarian Cancer Cells

Abstract Background It is known that the transcription factor zinc finger protein 703 (ZNF703) plays an important role in physiological functions and the occurrence and development of various tumors. However, the role and mechanism of ZNF703 in ovarian cancer are unclear. Materials and methods Immunohistochemistry was used to analyze the expression of ZNF703 in ovarian cancer patients and to assess the effect of ZNF703 expression on the survival and prognosis of ovarian cancer patients. ZNF703 overexpression and suppression expression experiments were used to evaluate the effect of ZNF703 on malignant biological behavior of ovarian cancer cells in vitro. Detecting the interaction between HE4 and ZNF703 by immunofluorescence colocalization and coprecipitation, and nuclear translocation. Chromatin immunoprecipitation-sequencing (ChIP-Seq), dual luciferase reporter assay, ChIP-PCR, in vivo model were applied to study the molecular mechanism of ZNF703 affecting the development of ovarian cancer. Results ZNF703 was highly expressed in ovarian cancer tissues, and its expression level is related to the prognosis of ovarian cancer patients. In vivo and in vitro experiments confirmed that ZNF703 overexpression/inhibition expression will promoted/inhibited the malignant biological behavior of ovarian cancer. Mechanically, ZNF703 interacted with HE4, and HE4 promoted nuclear translocation of ZNF703. ChIP-Seq identified multiple regulatory targets of ZNF703, of which ZNF703 directly binds to the enhancer region of PEA15 to promote the transcription of PEA15 and thereby promoted the proliferation of cancer cells. Conclusion The results showed that ZNF703 as an oncogene played an important role in the epigenetic modification of ovarian cancer proliferation, and suggested that ZNF703 as a transcription factor may become a prognostic factor and a potential therapeutic target for ovarian cancer.

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