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

Abstract

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 ET(A) receptor (ET(A)R), 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 ET(A)Rs, were used. As demonstrated by sub-G(1) 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 ET(A)R (BQ-123) and for ET(B)R (BQ-788). We showed that ET(A)R blockade inhibits the ET-1-induced survival activity against paclitaxel-mediated apoptosis. However, no effect was observed on blocking ET(B)R with BQ-788. Our results establish a novel role for ET-1 in determining survival of ovarian carcinoma cells and suggest that pharmacological ET(A)R blockade using a specific ET(A)R antagonist may provide a novel approach to the treatment of ovarian carcinoma in combination therapy.

Endothelin system in oral squamous carcinoma cells: Specific siRNA targeting of ECE‐1 blocks cell proliferation

“…Furthermore, it has been reported that ET-1 induces cell proliferation or antiapoptosis, via ET A R in NHEK, prostate and ovarian cancer cells, via ET B R in endothelial and melanoma, and via either receptor in colon cancer cells. 17,24,[27][28][29][30][31][32][33][34] In oral SCC cells, our results show that ET-1 can act via ET A R and/or ET B R for cell proliferation.…”

“…[26][27][28] It has been suggested that ET-1 aids tumour growth and the progression of various tumours by either promoting cell proliferation or by protecting cells from apoptosis. 27,[29][30][31][32][33][34] Cell proliferation and apoptosis must be balanced to maintain tissue homeostasis. However, cancer cells are often characterized by increased resistance to apoptosis, which enables their survival under abnormal growth stimulation and mediates their increased resistance to various forms of cellular stress, such as DNA damage, hypoxia or nutrient deprivation.…”

Bone-specific growth inhibition of prostate cancer metastasis by Atrasentan

“…ET-1 has been repeatedly shown to mediate survival and/or proliferation in cell-based assays, including prostate cancer cells. 13,[20][21][22] ET-1 has been shown to have direct angiogenic activity on cultured endothelial cells which enhanced the effect of vascular endothelial growth factor (VEGF) and is mediated primarily by ETB. 23,24 In vivo studies have yielded conflicting results, with ET-1 failing to induce angiogenesis in chick embryo chorioallantoic membrane and rat sponge models and inducing angiogenesis, via ETA, in a rat cornea model and, when combined with VEGF, in the matrigel plug and chick embryo chorioallantoic membrane assays.…”

Endothelin-1-induced Prostaglandin E2-EP2, EP4 Signaling Regulates Vascular Endothelial Growth Factor Production and Ovarian Carcinoma Cell Invasion

“…In ovarian cancer, endothelin-1 (ET-1) plays a key role in the development and progression of this tumor, promoting tumor cell proliferation (14,15), apoptosis protection (16), invasiveness (17), and neovascularization (18 -21). ET-1 and its selective receptor ET A (ET A R) are overexpressed in primary and metastatic ovarian carcinoma as compared with normal ovarian tissue (22).…”