scholarly journals The Impact of Integrin-Mediated Matrix Adhesion on Cisplatin Resistance of W1 Ovarian Cancer Cells

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 788 ◽  
Author(s):  
Kathleen Wantoch von Rekowski ◽  
Philipp König ◽  
Svenja Henze ◽  
Martin Schlesinger ◽  
Piotr Zawierucha ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cisplatin Resistance ◽  
Genetic Resistance ◽  
Collagen Type I ◽  
Ovarian Cancer Cells ◽  
Type I ◽  
Mrna Levels ◽  
Protein Levels ◽  
The Impact

Background: Tumor cell binding to the microenvironment is regarded as the onset of therapeutic resistance, referred to as cell adhesion mediated drug resistance (CAM-DR). Here we elucidate whether CAM-DR occurs in ovarian cancer cells and contributes to still-existing cisplatin resistance. Methods: Cultivation of W1 and cisplatin-resistant W1CR human ovarian cancer cells on collagen-type I (COL1) was followed by whole genome arrays, MTT assays focusing cisplatin cytotoxicity, and AAS detection of intracellular platinum levels. Expression of cisplatin transporters Ctr1 and MRP2 was analyzed. Mechanistic insight was provided by lentiviral β1-integrin (ITGB1) knockdown, or inhibition of integrin-linked kinase (ILK). Results: EC50 values of cisplatin cytotoxicity increased twofold when W1 and W1CR cells were cultivated on COL1, associated with significantly diminished intracellular platinum levels. Transporter deregulation could not be detected at mRNA levels but appears partially responsible at protein levels. The ITGB1 knockdown confirms that CAM-DR follows a COL1/ITGB1 signaling axis in W1 cells; thus, a blockade of ILK re-sensitized W1 cells on COL1 for cisplatin. In contrast, CAM-DR adds to cisplatin resistance in W1CR cells independent of ITGB1. Conclusions: CAM-DR appears relevant for ovarian cancer cells, adding to existing genetic resistance and thus emerges as a target for sensitization strategies.

scholarly journals Circular RNA MTO1 inhibits the proliferation and invasion of ovarian cancer cells through the miR-182-5p/KLF15 axis

2020 ◽  
Author(s):  
Ning Wang ◽  
Qin-Xue Cao ◽  
Jun Tian ◽  
Lu Ren ◽  
Hai-Ling Cheng ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Circular Rna ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Ovarian Cancer Cells ◽  
Mrna Levels ◽  
Protein Levels ◽  
Proliferation And Invasion

Abstract Background: Circular RNAs (circRNAs) are a novel class of endogenous noncoding RNAs and have been shown to play important roles in a variety of physiological processes. Recently, dysregulation of circRNAs has been identified in many types of cancers. In this study, we analyzed the expression profile and biological functions of circMTO1 in ovarian cancer. Materials and methods: Cell proliferation and invasion were assessed by CCK-8 and transwell assay, respectively. The RT-qPCR analysis was performed to measure mRNA levels of circMTO1 and miR-182-5p. The western blot was used to detect KLF15 protein levels. Luciferase reporter assays were performed to determine the interaction between LINC00958 and miR-204-3p and the interaction between miR-204-3p and KIF2A. Results: We demonstrated that circMTO1 was down-regulated in ovarian cancer tissues and cell lines. Up-regulation of circMTO1 inhibited proliferation and invasion of ovarian cancer cells while down-regulation of circMTO1 promoted these processes. Mechanistically, we showed that circMTO1 sponged miR-182-5p to support KLF15 expression, eventually leading to inhibition of ovarian cancer progression. Conclusions: Our study suggested circMTO1 as a novel biomarker and therapeutic target for ovarian cancer treatment.

scholarly journals HOTTIP-miR-205-ZEB2 Axis Confers Cisplatin Resistance to Ovarian Cancer Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Yu-Jie Dong ◽  
Wei Feng ◽  
Yan Li
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cisplatin Resistance ◽  
Clinical Problem ◽  
Ovarian Cancer Cells ◽  
Stem Cell Markers ◽  
Gene Target ◽  
Gynecological Malignancy ◽  
Clonogenic Potential ◽  
Resistant Cells

Ovarian cancer is a deadly gynecological malignancy with resistance to cisplatin a major clinical problem. We evaluated a role of long non-coding (lnc) RNA HOTTIP (HOXA transcript at the distal tip) in the cisplatin resistance of ovarian cancer cells, using paired cisplatin sensitive and resistant A2780 cells along with the SK-OV-3 cells. HOTTIP was significantly elevated in cisplatin resistant cells and its silencing reversed the cisplatin resistance of resistant cells. HOTTIP was found to sponge miR-205 and therefore HOTTIP silenced cells had higher levels of miR-205. Downregulation of miR-205 could attenuate HOTTIP-silencing effects whereas miR-205 upregulation in resistant cells was found to re-sensitize cells to cisplatin. HOTTIP silencing also led to reduced NF-κB activation, clonogenic potential and the reduced expression of stem cell markers SOX2, OCT4, and NANOG, an effect that could be attenuated by miR-205. Finally, ZEB2 was identified as the gene target of miR-205, thus completing the elucidation of HOTTIP-miR-205-ZEB2 as the novel axis which is functionally involved in the determination of cisplatin resistance in ovarian cancer cells.

scholarly journals Insight into Cisplatin-Resistance Signaling of W1 Ovarian Cancer Cells Emerges mTOR and HSP27 as Targets for Sensitization Strategies

2020 ◽  
Vol 21 (23) ◽  
pp. 9240
Author(s):  
Kathleen Wantoch von Rekowski ◽  
Philipp König ◽  
Svenja Henze ◽  
Martin Schlesinger ◽  
Piotr Zawierucha ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cisplatin Resistance ◽  
Mapk Pathway ◽  
Ovarian Cancer Cells ◽  
Strong Impact ◽  
Intrinsic Resistance ◽  
Western Blots ◽  
Collagen Type 1 ◽  
Signaling Components

The microenvironment possesses a strong impact on the tumor chemoresistance when cells bind to components of the extracellular matrix. Here we elucidate the signaling pathways of cisplatin resistance in W1 ovarian cancer cells binding to collagen type 1 (COL1) and signaling interference with constitutive cisplatin resistance in W1CR cells to discover the targets for sensitization. Proteome kinase arrays and Western blots were used to identify the signaling components, their impact on cisplatin resistance was evaluated by inhibitory or knockdown approaches. W1 cell binding to COL1 upregulates integrin-associated signals via FAK/PRAS40/mTOR, confirmed by β1-integrin (ITGB1) knockdown. mTOR appears as key for resistance, its blockade reversed COL1 effects on W1 cell resistance completely. W1CR cells compensate ITGB1-knockdown by upregulation of discoidin domain receptor 1 (DDR1) as alternative COL1 sensor. COL1 binding via DDR1 activates the MAPK pathway, of which JNK1/2 appears critical for COL1-mediated resistance. JNK1/2 inhibition inverts COL1 effects in W1CR cells, whereas intrinsic cisplatin resistance remained unaffected. Remarkably, knockdown of HSP27, another downstream MAPK pathway component overcomes intrinsic resistance completely sensitizing W1CR cells to the level of W1 cells for cisplatin cytotoxicity. Our data confirm the independent regulation of matrix-induced and intrinsic chemoresistance in W1 ovarian cancer cells and offer novel targets for sensitization.

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