Abstract
Emerging evidence suggests molecular and phenotypic association between chemoresistance and epithelial-mesenchymal transition (EMT) in cancer. Endothelin-1 (ET-1)/endothelin A receptor (ET(A)R) axis is implicated in the pathobiology of epithelial ovarian cancer (EOC) by driving tumor-promoting effects, including EMT. Here, we analyzed how ET(A)R regulates chemoresistance and EMT in EOC. The effects of ET-1 axis on cell proliferation, drug-induced apoptosis, invasiveness, and EMT were analyzed in cultured EOC cells sensitive and resistant to cisplatinum and taxol. Tumor growth in response to ET(A)R antagonist was examined in EOC xenografts. ET(A)R expression was examined in 60 human EOC tumors by immunohistochemistry and correlated with chemoresistance and EMT. In resistant EOC cells ET-1 and ET(A)R are upregulated, paralleled by enhanced mitogen activated protein kinase (MAPK) and Akt phosphorylation and cell proliferation. Moreover, in these cells the expression of E-cadherin transcriptional repressors, including Snail, Slug, and Twist, as well as of mesenchymal markers, such as vimentin and N-cadherin, were upregulated and linked with enhanced invasive behavior. Interestingly, ET(A)R blockade with zibotentan, a specific ET(A)R antagonist, or its silencing, downregulated Snail activity, restored drug sensitivity to cytotoxic-induced apoptosis, and inhibited the invasiveness of resistant cells. In vivo, zibotentan inhibited tumor growth of sensitive and resistant EOC xenografts, and sensitized to chemotherapy. Analysis of EOC human tissues revealed that ET(A)R is overexpressed in resistant tumors and is associated with EMT phenotype. Our data provide the first evidence that blockade of ET(A)R-driven EMT can overcome chemoresistance and inhibit tumor progression, improving the outcome of EOC patients' treatment.
Highlights
Ovarian cancer accounts for the highest tumor-related mortality in women with gynaecologic malignancy [1]
Our data provide the first evidence that blockade of endothelin A receptor (ETAR)-driven epithelial–mesenchymal transition (EMT) can overcome chemoresistance and inhibit tumor progression, improving the outcome of epithelial ovarian cancer (EOC) patients’ treatment
In view of the above, in this study we evaluated whether response to chemotherapeutics in sensitive, and cisplatin- and taxol-resistant EOC cells and in human tissues is associated with the activation of ET-1/ETAR signaling, EMT and invasive phenotype and activation of survival signaling pathways
Summary
Ovarian cancer accounts for the highest tumor-related mortality in women with gynaecologic malignancy [1]. The identification of the molecular mechanisms underlying chemoresistance is mandatory to achieve advancement in ovarian cancer therapy [2]. Accumulating evidences demonstrated that epithelial–mesenchymal transition (EMT), which modulates cancer progression and metasta-. The E-cadherin repressors, Snail and Slug, which interact with E-box elements located within the proximal region of the E-cadherin promoter, and the basic helix-loop-helix transcription factor Twist, are significant inducers of EMT in cancer cells by repressing E-cadherin expression [5]. Several clinical studies have shown that increased expression of E-cadherin is associated with improved survival in several tumor types [6, 7], and silencing of E-cadherin transcriptional suppressors can increase cellular sensitivity to genotoxic stress [8]. Since EMT development is driven by key modulators that are directly controlled by numerous extracellular signals and pathways [5], it is becoming clear that the blockade of these signaling pathways is critical for
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