Title:The Endothelin Axis as Therapeutic Target in Human Malignancies: Present and Future
Volume: 18
Issue: 19
Author(s): Anna Bagnato
Affiliation:
Keywords:
Endothelin, endothelin receptor, epithelial-mesenchymal transition, β-arrestin, cancer therapy, chemoresistance, G-protein coupled receptor (GPCR), pleiotropic effects, cytotoxic drugs, malignancies
Abstract: To assure their growth advantage cancer cells require the appropriation of key pathways, such as those controlled by G-protein
coupled receptor (GPCR), that influence cell growth, migration, and death, as well as the expansion of vascular networks. Accumulating
molecular and in vivo evidences demonstrate that the activation of the endothelin-1 (ET-1) axis elicites pleiotropic effects on tumour cells
and on the tumour microenvironment as well, modulating epithelial to mesenchymal transition, chemoresistance, and other tumourassociated
processes. As ET-1 axis blockade has been shown to reduce tumor growth in preclinical models, several small molecule antagonists
of ET-1 receptors are currently undergoing clinical trial as novel agents in cancer therapy. To fully appreciate the potential
hegemony of the ET-1 axis in cancer, here we review emerging preclinical and clinical data outlining the spectrum of cellular activities
triggered by ET-1 signaling and the challenges facing molecular targeted therapy. Because scaffold proteins, such as β-arrestin, create
signalling platforms that drive cellular transformation upon GPCR activation, mechanisms mediated by β-arrestin in ET-1 signalling are
discussed. Deeper understanding of molecular mechanisms activated by ET-1 receptor, as well as of how pathway crosstalk can influence
ET-1 signalling outcome in cancer, is of paramount translational relevance in the study of ET-1 receptor-targeted therapy. The improved
knowledge of the interconnected molecular mechanism promoted by ET-1 axis in cancer will certainly result in more effective and
durable mechanism-guided combinations of ET-1 receptor antagonists with cytotoxic drugs or other targeted agents in the clinical management
of ET-1 axis-dependent malignancies.