Signaling network in focus
The endothelin axis in cancer

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Abstract

The endothelin axis, comprising endothelins and their receptors, has recently emerged as relevant player in tumor growth and metastasis by regulating mitogenesis, cell survival, angiogenesis, bone remodeling, stimulation of nociceptor receptor, tumor-infiltrating immune cells, epithelial-to-mesenchymal transition, invasion and metastatic dissemination. Endothelin-1 participates in the growth and progression of a variety of tumors such as prostatic, ovarian, renal, pulmonary, colorectal, cervical, breast, bladder, endometrial carcinomas, Kaposi's sarcoma, brain tumors, melanoma, and bone metastases. This review highlights key signaling pathways activated by endothelin-1 axis in cancer, since the understanding the full spectrum activated by endothelin-1 is critical for the optimal design of targeted therapies. Preliminary experimental and clinical data demonstrate that interfering with endothelin receptor by using endothelin-1 receptor antagonists alone and in combination with cytotoxic drugs or molecular inhibitors could represent a new mechanism-based antitumor strategy.

Introduction

Endothelins (ETs) are a family of three 21-aa peptides ET-1, ET-2 and ET-3. ETs mediate their action by activating two G-protein-coupled receptor (GPCR) subtypes, ETA receptor (ETAR) and ETB receptor (ETBR). In addition to its role as a potent endogenous vasoconstrictor and mediator of cardiovascular and renal disorders, the endothelin axis has a relevant role in various cancer cells and stromal cells leading to autocrine/paracrine loops that activate aberrant proliferation, escape from apoptosis, new vessels formation, immune modulation, abnormal osteogenesis, alteration of nociceptive stimuli, invasion and metastatic dissemination (Fig. 1) (Nelson, Bagnato, Battistini, & Nisen, 2003).

Section snippets

Synthesis

ET-1, ET-2 and ET-3 are characterized by a single α-helix and two disulfide bridges. ET-1 and ET-2 have similar structures, whereas ET-3 differs in structure at 6 of 21 aa. The three peptides are encoded by distinct genes and are regulated at the level of mRNA transcription. The primary translation product of the ET-1 gene is the 212-aa prepro-ET-1, which is cleaved by an endothelin converting enzyme (ECE-1) to form the 38-aa big-ET-1, and then to the biologically active peptide and a C-terminal

Endothelin receptors and G-protein signaling

ETs exert their effects by binding to two distinct cell surface ET receptors, ETAR and ETBR. ETBR has equal affinities for either ETs, whereas ETAR exhibits an affinity for ET-3 that is two orders of magnitude lower than that for ET-1 and ET-2. Most important, ligand activation of ETBR leads to induction of intracellular pathways being counter-regulatory to ETAR signaling. The receptors belong to the superfamily of GPCR and contain seven hydrophobic transmembrane domains, an intracytoplasmatic

Targeting endothelin receptor as novel approach in cancer treatment

The demonstration that ET-1 actions are concordant with many of the “hallmarks of cancer” indicates a critical role for ET-1 in the initiation or progression of many tumors clearly identifying the ET axis as a potential therapeutic target. This has propelled the development of several approaches targeting ET-1 axis in cancer therapy including ECE inhibitors or NEP transfection, which efficiently degrades ET-1, or selective or non-selective antagonists for ETAR and ETBR (Smollich & Wulfing, 2007

Conclusion

The endothelin axis has a crucial role in stromal-cancer cell interactions that promote tumor initiation and progression representing a new and mostly unexplored target for cancer therapy. ET-1 receptor antagonism remains a promising therapeutic approach. However in some tumors it is still unclear when to use selective ETAR antagonists and when to use mixed ETA/BR blockers. To this end, further information regarding the expression of endothelin receptors in different neoplasia is required.

Acknowledgements

We thank F. Spinella, V. Di Castro and M.R. Nicotra for their contributions to studies on cancer cells, P.G. Natali for valuable comments and M.V. Sarcone for secretarial assistance. This work was supported by the Associazione Italiana Ricerca sul Cancro, Ministero della Salute and CNR-MIUR.

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