Understanding and overcoming chemoresistance in ovarian cancer: emerging role of the endothelin axis.

cancer cells integrate multiple signalling pathways sustaining tumor progression, therapeutic interest in the endothelin-1 (ET-1)/endothelin A receptor (ETAR) axis is supported by its central role in several human cancers, including eoc, in which its overexpression correlates with advanced stages 4. In eoc cells, the autocrine loop mediated by the ET-1/ETAR interaction has been implicated in the sustained activation of cell proliferation; escape from apoptosis; and angiogenesis, emt, invasion, and metastasis 5. In chemoresistant eoc cells, ET-1 and ETAR are upregulated, paralleled by enhanced mapk and Akt phosphorylation, cell proliferation, and reduced sensitivity to cytotoxic drugs, paclitaxel, and cisplatin 6. It is becoming clear that emt may reflect an ultimate adaptation of cancer cells to survive cytotoxic drug activity, and may thus be responsible for chemosensitivity 3. In human eoc, changes in the expression of Snail, Slug, and Twist play an important role in ovarian tumorigenesis and progression; expression is significantly higher in advanced stages and in metastatic lesions 7,8. Moreover, cellular morphology, motility, and molecular changes consistent with emt, including enhanced expression of Snail and Twist, were reported to be related to paclitaxel resistance in eoc cells 9,10. In our recent study, we reported that, compared with parental cells, resistant eoc cells showed enhanced expression levels of mesenchymal markers Snail, Slug, Twist, vimentin, and N-cadherin, and that the enhanced expression was associated with a concomitant decrease in E-cadherin expression 6. Moreover, ET-1 enhanced the expression of Snail and Twist, and treatment with the selective ETAR antagonist zibotentan inhibited the ET-1–induced effects, restoring E-cadherin expression. Remarkably, ETAR blockade, either by zibotentan or by silencing, reverted the ET-1–induced suppression of E-cadherin promoter activity, suggesting that transcriptional regulation of E-cadherin may be important to ETARdriven emt and acquisition of chemoresistance. KEY WORDS