Resistance to platinum-based chemotherapy is associated with epithelial to mesenchymal transition in epithelial ovarian cancer

Marchini, Sergio; Fruscio, Robert; Clivio, Luca; Beltrame, Luca; Porcu, Luca; Nerini, Ilaria Fuso; Cavalieri, Duccio; Chiorino, Giovanna; Cattoretti, Giorgio; Mangioni, Costantino; Milani, Rodolfo; Torri, Valter; Romualdi, Chiara; Zambelli, Alberto; Romano, Michela; Signorelli, Mauro; Giandomenico, Silvana Di; D’Incalci, Maurizio

doi:10.1016/j.ejca.2012.06.026

Cited by 146 publications

(145 citation statements)

References 23 publications

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“…LPA regulates a multitude of ovarian tumor cell responses, including proliferation, migration, and invasion (19,24,28). LPA is expressed as high as 80 M in the ascites fluid and serum of patients with ovarian cancer (24, 25, 49 -51), underlying the importance of understanding its pathophysiological role in ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

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Lysophosphatidic Acid Initiates Epithelial to Mesenchymal Transition and Induces β-Catenin-mediated Transcription in Epithelial Ovarian Carcinoma

Burkhalter¹,

Westfall

Liu

et al. 2015

Journal of Biological Chemistry

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Background: Aberrant activation of Wnt/␤-catenin signaling is found in ovarian cancer, even when mutations are absent. Results: The bioactive lipid lysophosphatidic acid induces ␤1-integrin clustering, nuclear ␤-catenin translocation, and activation of Tcf/Lef-regulated gene expression. Conclusion: Microenvironmental lipids modulate ␤-catenin signaling. Significance: Understanding the mechanisms of Wnt/␤-catenin activation provides a basis for therapeutic targeting of the pathway in ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

“…(EMT), and it is proposed that this phenotypic plasticity contributes to decreased response to conventional therapeutics (17)(18)(19)(20). Furthermore, recent work has demonstrated a role for the mesenchymal phenotype in mesothelial cell invasion at metastatic sites in the peritoneal cavity (21).…”

mentioning

confidence: 99%

Lysophosphatidic Acid Initiates Epithelial to Mesenchymal Transition and Induces β-Catenin-mediated Transcription in Epithelial Ovarian Carcinoma

Burkhalter¹,

Westfall

Liu

et al. 2015

Journal of Biological Chemistry

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“…Understanding the distinct mechanisms that facilitate survival and propagation is therefore central for improving the clinical outcome for patients with EOC. Emerging evidences suggest that epithelial-mesenchymal transition (EMT) plays a crucial role in the aggressiveness of EOC, because it increases migration and invasion ability, contributing to chemoresistance and cancer stem cell (CSC) populations (3,4). Among the proteins driving tumor progression and EMT, numerous studies have identified G protein-coupled receptors (GPCR) as the most prominent validated pharmacologic targets in biomedicine (5).…”

Section: Introductionmentioning

confidence: 99%

Endothelin A Receptor/β-Arrestin Signaling to the Wnt Pathway Renders Ovarian Cancer Cells Resistant to Chemotherapy

Rosanò¹,

Cianfrocca²,

Tocci³

et al. 2014

Cancer Research

107

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The high mortality of epithelial ovarian cancer (EOC) is mainly caused by resistance to the available therapies. In EOC, the endothelin-1 (ET-1, EDN1)-endothelin A receptor (ET A R, EDNRA) signaling axis regulates the epithelial-mesenchymal transition (EMT) and a chemoresistant phenotype. However, there is a paucity of knowledge about how ET-1 mediates drug resistance. Here, we define a novel bypass mechanism through which ET A R/b-arrestin-1 (b-arr1, ARRB1) links Wnt signaling to acquire chemoresistant and EMT phenotype. We found that ET A R/b-arr1 activity promoted nuclear complex with b-catenin and p300, resulting in histone acetylation, chromatin reorganization, and enhanced transcription of genes, such as ET-1, enhancing the network that sustains chemoresistance. Silencing of b-arr1 or pharmacologic treatment with the dual ET A R/ET B R antagonist macitentan prevented core complex formation and restored drug sensitivity, impairing the signaling pathways involved in cell survival, EMT, and invasion. In vivo macitentan treatment reduced tumor growth, vascularization, intravasation, and metastatic progression. The combination of macitentan and cisplatinum resulted in the potentiation of the cytotoxic effect, indicating that macitentan can enhance sensitivity to chemotherapy. Investigations in clinical specimens of chemoresistant EOC tissues confirmed increased recruitment of b-arr1 and b-catenin to ET-1 gene promoter. In these tissues, high expression of ET A R significantly associated with poor clinical outcome and chemoresistance. Collectively, our findings reveal the existence of a novel mechanism by which ET A R/b-arr1 signaling is integrated with the Wnt/b-catenin pathway to sustain chemoresistance in EOC, and they offer a solid rationale for clinical evaluation of macitentan in combination with chemotherapy to overcome chemoresistance in this setting. Cancer Res; 74(24); 7453-64. Ó2014 AACR.

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“…VIM was selected for the following reasons: Firstly, it is well known that VIM is an essential constituent of cytoskeletal proteins of mesenchymal cells and VIM is a marker of epithelial-mesenchymal transition (EMT) (29). Many studies have shown that EMT is critical for chemoresistance, particularly in ovarian cancer (30,31). Secondly, VIM has a putative miR-134 target site in its CDS region.…”

Section: Discussionmentioning

confidence: 99%

Hybrid-polymerase chain reaction to identify novel target genes of miR-134 in paclitaxel resistant human ovarian carcinoma cells

Shuang¹,

Wang²,

Chang³

2015

Oncology Letters

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Abstract.Increasing evidence has shown that miR-134 is involved in the promotion of tumorigenesis and chemoresistance. However, whether miR-134 participates in ovarian cancer chemoresistance and its functional targets still remains unclear. The objective of this study was to apply hybrid-polymerase chain reaction (PCR) to screen target genes of miR-134 in ovarian carcinoma paclitaxel resistant SKOV3-TR30 cells, and to provide a number of novel targets of miR-134 for further study of ovarian cancer paclitaxel resistance. The current study found that miR-134 was decreased in SKOV3-TR30 cells compared with the parental SKOV3 cell line. By applying hybrid-PCR, 8 putative target genes of miR-134 in SKOV3-TR30 cells were identified, including C16orf72, PNAS-105, SRM, VIM, F-box protein 2, GAPDH, PRPF6 and RPL41. Notably, the target sites of VIM and PRPF6 were not located in 3'untranslated region, but rather in the coding sequence region. By conducting a luciferase reporter assay, miR-134 was demonstrated to recognize the putative binding sites of these target genes including VIM and PRPF6. Transfecting SKOV3-TR30 cells with miR-134 mimic and performing reverse transcription-PCR in addition to western blot analysis confirmed that miR-134 regulates vimentin expression at a post transcriptional level. This finding provides a novel perspective for studying the mechanism of miR-134/mRNA interaction. In conclusion, this study was the first to apply an effective method of hybrid-PCR to screen putative target mRNAs of miR-134 in paclitaxel resistant SKOV3-TR30 cells and indicate that miR-134 may contribute to the induction of SKOV3-TR30 paclitaxel resistance by targeting these genes.

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Resistance to platinum-based chemotherapy is associated with epithelial to mesenchymal transition in epithelial ovarian cancer

Cited by 146 publications

References 23 publications

Lysophosphatidic Acid Initiates Epithelial to Mesenchymal Transition and Induces β-Catenin-mediated Transcription in Epithelial Ovarian Carcinoma

Lysophosphatidic Acid Initiates Epithelial to Mesenchymal Transition and Induces β-Catenin-mediated Transcription in Epithelial Ovarian Carcinoma

Endothelin A Receptor/β-Arrestin Signaling to the Wnt Pathway Renders Ovarian Cancer Cells Resistant to Chemotherapy

Hybrid-polymerase chain reaction to identify novel target genes of miR-134 in paclitaxel resistant human ovarian carcinoma cells

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