Endothelin-1 acts as a survival factor in ovarian carcinoma cells

The aim of this study was to evaluate the role of endothelin-1 (ET-1) in the sensitivity of ovarian carcinoma to paclitaxel, one of the most common drugs used for the management of this tumour histotype. ET-1 is a powerful mitogenic peptide produced by ovarian carcinomas and it acts as an autocrine growth factor, selectively through ETA receptor (ETAR), which is predominantly expressed in this tumour. OVCA 433 and HEY, two ovarian carcinoma cell lines, which produce elevated amounts of ET-1 and express abundantly high-affinity ETARs, were used. As demonstrated by sub-G1 peak in DNA content histograms and terminal transferase deoxytidyl uridine end labelling assay, we found that paclitaxel induces cytotoxic effect through the activation of apoptosis in both cell lines. When the treatment with paclitaxel was performed in association with ET-1, paclitaxel-induced apoptosis was inhibited. In order to evaluate which ET-1 receptor mediated the effect of ET-1 on protection from paclitaxel-induced apoptosis, we performed experiments using two selective antagonists for ETAR (BQ-123) and for ETBR (BQ-788). We showed that ETAR blockade inhibits the ET-1-induced survival activity against paclitaxel-mediated apoptosis. However, no effect was observed on blocking ETBR with BQ-788. Our results establish a novel role for ET-1 in determining survival of ovarian carcinoma cells and suggest that pharmacological ETAR blockade using a specific ETAR antagonist may provide a novel approach to the treatment of ovarian carcinoma in combination therapy.

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Endothelin-1 Protects Ovarian Carcinoma Cells against Paclitaxel-Induced Apoptosis: Requirement for Akt Activation

Molecular Pharmacology ◽

10.1124/mol.61.3.524 ◽

2002 ◽

Vol 61 (3) ◽

pp. 524-532 ◽

Cited By ~ 110

Author(s):

Donatella Del Bufalo ◽

Valeriana Di Castro ◽

Annamaria Biroccio ◽

Marco Varmi ◽

Debora Salani ◽

...

Keyword(s):

Ovarian Carcinoma ◽

Carcinoma Cells ◽

Akt Activation ◽

Endothelin 1 ◽

Ovarian Carcinoma Cells ◽

Induced Apoptosis

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Effect of Neopterin Derivatives on Mitochondrial Dehydrogenase Activity in Ovarian Carcinoma Cell Lines in Vitro

Pteridines ◽

10.1515/pteridines.2006.17.4.115 ◽

2006 ◽

Vol 17 (4) ◽

pp. 115-120 ◽

Cited By ~ 1

Author(s):

Josef Rieder ◽

Christian Marth ◽

Georg Hoffmann'

Keyword(s):

Ovarian Carcinoma ◽

Dehydrogenase Activity ◽

Cell Lines ◽

Carcinoma Cell ◽

Redox Status ◽

Carcinoma Cells ◽

Carcinoma Cell Lines ◽

Ovarian Carcinoma Cells ◽

Mitochondrial Dehydrogenase Activity

Abstract In a recent study we could show that neopterin inhibits nitric oxide-induced apoptosis in ovarian carcinoma cells. This may provide an explanation for the correlation between increased levels of neopterin derivatives and the unfavorable prognosis in patients with ovarian cancer that has been described in the literature. To obtain additional information on the mode of action of neopterin derivatives within the tumor environment, we studied the effects of neopterin (100 and 1000 μΜ) and 7,8-dihydroneopterin (100, 500, and 1000 μΜ) on mitochondrial dehydrogenase activity in three different ovarian carcinoma cell lines (2774, HOC-1, and OVCAR-3). 7,8-dihydroneopterin was an effective stimulus of mitochondrial enzyme turnover rate in any cell culture model under investigation. This suggests that the pteridine compound stabilizes tumor cell viability and therefore acts as a promotor of tumor growth. In contrast to 7.8-dihydroneopterin, neopterin did not affect mitochondrial dehydrogenases in 2774, HOC-7, or OVCAR-3 cells. However, in HOC-7 and OCVAR-3, neopterin was found to antagonize the stimulating effects of 7,8-dihydroneopterin. This might be due to the different impact of both pteridine compounds on the redox status in these cells. Our new data provide further evidence of distinct biochemical effects of neopterin derivatives in ovarian carcinoma cells. Neopterin and 7,8-dihydroneopterin may be involved in separate stages of cellular changes that lead to malignancy or promote tumor progression.

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Smad4 induces cell death in HO-8910 and SKOV3 ovarian carcinoma cell lines via PI3K-mTOR involvement

Experimental Biology and Medicine ◽

10.1177/1535370220916709 ◽

2020 ◽

Vol 245 (9) ◽

pp. 777-784

Author(s):

Yushuang Yao ◽

Zhe Zhang ◽

Fanmao Kong ◽

Zhuqing Mao ◽

Zhaoyuan Niu ◽

...

Keyword(s):

Cell Viability ◽

Ovarian Carcinoma ◽

Cell Lines ◽

Molecular Mechanisms ◽

Treatment Strategies ◽

Carcinoma Cells ◽

Skov3 Cell ◽

Ovarian Carcinoma Cells ◽

Skov3 Cells ◽

Induced Apoptosis

Ovarian carcinoma is one of the most common malignant cancers in women. Previous research has shown that Smad4 participates in the progression of multiple biological reactions as a crucial regulator. Nevertheless, studies on the role of Smad4 in ovarian carcinoma have been extremely limited. The study aim was to explore the mechanism underlying Smad4 regulation of HO-8910 and SKOV3 cell viability and autophagy. We observed that Smad4 gene expression in ovarian carcinoma tissues and cell lines was downregulated, and Smad4 overexpression resulted in decreased proliferation and increased autophagy in HO-8910 and SKOV3 cells (ovarian carcinoma cells). We also found that Smad4 overexpression induced apoptosis of ovarian carcinoma cells. A co-immunoprecipitation assay also revealed that Smad4 interacted with the P85 subunit of PI3K and caused its degradation and dephosphorylation. Subsequently, expression of mTOR was inhibited. Accordingly, these findings showed that further investigation of the biological mechanisms underlying ovarian carcinoma occurrence and progression is warranted, which may lead to new ovarian carcinoma treatment strategies. Impact statement This study investigated the effect and mechanism of Smad4 in ovarian carcinoma (OC) cell viability and demonstrated that Smad4 acted as a tumor suppressor in OC, which may contribute to the understanding of molecular mechanisms underlying OC occurrence and progression. Smad4 expression was decreased in the OC specimens, but Smad4 recovery in the OC cell lines impaired the survival and viability of OC cells by increasing autophagy and apoptosis. Further investigation showed that Smad4 interacted with the P85 subunit of PI3K and caused deactivation of the PI3K/mTOR pathway. Therefore, Smad4 could be considered as a target in cancer therapy due to its regulatory effect in OC carcinogenesis.

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Mechanism of taxol-induced apoptosis in human SKOV3 ovarian carcinoma cells

Journal of Cellular Biochemistry ◽

10.1002/jcb.20006 ◽

2004 ◽

Vol 91 (5) ◽

pp. 1043-1052 ◽

Cited By ~ 43

Author(s):

Hak Jun Ahn ◽

Yeong Shik Kim ◽

Joung-Uk Kim ◽

Sung Min Han ◽

Jin Woo Shin ◽

...

Keyword(s):

Ovarian Carcinoma ◽

Carcinoma Cells ◽

Ovarian Carcinoma Cells ◽

Induced Apoptosis

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ABT-627, a potent endothelin receptor A antagonist, inhibits ovarian carcinoma growth in vitro

Clinical Science ◽

10.1042/cs103s318s ◽

2002 ◽

Vol 103 (s2002) ◽

pp. 318S-321S ◽

Cited By ~ 17

Author(s):

Debora SALANI ◽

Laura ROSANÒ ◽

Valeriana DI CASTRO ◽

Francesca SPINELLA ◽

Aldo VENUTI ◽

...

Keyword(s):

Growth Factor ◽

Ovarian Carcinoma ◽

Cell Lines ◽

Primary Cultures ◽

Multidisciplinary Treatment ◽

Ovarian Tumour ◽

Tumour Cells ◽

Ovarian Carcinomas ◽

Novel Approach

Endothelin-1 (ET-1) is present at high concentrations in ovarian cancer ascites and is overexpressed in primary and metastatic ovarian carcinomas. In these tumours the presence of ET-1 is associated with enhanced neovascularization and with vascular endothelial growth factor (VEGF) expression. In these tumour cells, ET-1 acts as an autocrine growth factor selectively through the receptor ETA, which is predominantly expressed in tumour cells. Furthermore, ET-1 produced by ovarian tumour cells stimulates VEGF production and VEGF-mediated angiogenic effects through ETA binding. These results demonstrate that activation of the ETA in ovarian carcinoma cells promotes cell proliferation, neovascularization and invasion, which are the principal hallmarks of malignant transformation. The present study was designed to investigate the effects of the ETA-selective antagonist ABT-627 on the ET-1-induced mitogenic effect in both primary cultures (PMOV1 and PMOV2) and cell lines (OVCA 433 and HEY) of ovarian carcinoma. All tumour cells express the components of the ET-1 system and secrete ET-1. ETA blockade by ABT-627 inhibits ET-1-induced mitogenic effects. The ETB antagonist BQ-788 is ineffective although all cell lines express both ETA and ETB mRNAs. In conclusion, our results demonstrate that ABT-627 is capable of inhibiting the proliferative activity of ET-1, suggesting that this potent ETA antagonist may provide a novel approach to the multidisciplinary treatment of ovarian carcinoma.

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Autocrine regulation of growth stimulation in human epithelial ovarian carcinoma by serine-proteinase-catalysed release of the urinary-type-plasminogen-activator N-terminal fragment

Biochemical Journal ◽

10.1042/bj3410765 ◽

1999 ◽

Vol 341 (3) ◽

pp. 765-769 ◽

Cited By ~ 5

Author(s):

David A. FISHMAN ◽

Alicia KEARNS ◽

Susan LARSH ◽

Jan J. ENGHILD ◽

M. Sharon STACK

Keyword(s):

Ovarian Carcinoma ◽

Plasminogen Activator ◽

Proteinase Inhibitors ◽

Serine Proteinase ◽

Carcinoma Cells ◽

Single Chain ◽

Ovarian Carcinomas ◽

Ovarian Carcinoma Cells ◽

Terminal Fragment ◽

Type Plasminogen Activator

Ovarian carcinomas secrete single-chain urinary-type plasminogen activator (scuPA) and expression of uPA is up-regulated relative to normal ovarian epithelium, leading to an enhanced proteolytic capacity which may facilitate invasion. Furthermore, the uPA receptor (uPAR) is present on ovarian carcinoma cells and is occupied in tumour tissues. In the present study, incubation of scuPA with serum-free conditioned medium from ovarian carcinoma cells resulted in release of a 14 kDa polypeptide. N-terminal sequence analysis identified this fragment as the uPA N-terminal fragment (NTF), which contains a growth-factor and a kringle domain. NTF generation was abolished by serine-proteinase inhibitors, but not inhibitors of matrix metalloproteinases, and was not enhanced by the addition of plasminogen or plasmin. To determine whether ovarian carcinoma-cell growth is altered by uPA, the effect of exogenous scuPA or NTF on proliferation was analysed. Both NTF and scuPA induced a dose-dependent increase in proliferation, with maximal stimulation obtained at 10-20 nM. Furthermore, blocking the interaction of endogenous uPA with uPAR using anti-NTF antibodies significantly inhibited proliferation. Together these data indicate that, in addition to enhancing the invasive activity of ovarian carcinoma cells via increased pericellular proteolysis, uPA also acts as a mitogen for ovarian carcinoma cells, suggesting a biochemical mechanism whereby uPA may contribute to ovarian carcinoma progression by modulating both cell invasion and proliferation.

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