Modulator - Issue No. 18

Endothelins and Urotensin II

Ofra Gohar, Ph.D.

Endothelins (ET-1,2,3) and Urotensin II are peptides that are considered to be very powerful vasoconstrictive substances. In humans, endothelins mediate their actions via two specific G-Protein coupled receptors, ETAR and ETBR. Both ETAR and ETBR are present in the heart and in human myocardium at similar levels.1,2

Powerful vasoconstrictors and tumor growth stimulators

Until recently it was thought that all cellular activities of the endothelins were mediated through their interactions with their cell surface receptors. However, a recent study demonstrated that cardiac nuclei also possess both ETAR and ETBR subtypes, which are functional and coupled to signaling mechanisms within the nuclear membrane2. The endothelin receptors differ in their ligand specificity. While ETAR has varying affinities for the endothelin isoforms (ET-1 >ET-2>ET-3), ETBR shows no selective affinity2,3. Subsequent studies have demonstrated the presence of endothelins in vascular as well as in non-vascular cells and tissues, having multiple biological activities.

The human Urotensin II receptor (UTIIR) was originally isolated as an orphan receptor (GPR14) in neural and sensory tissues. Urotensin II is expressed in various human tissues such as CNS, skeletal muscle, pancreas, and heart4-6. The role and the importance of ET-1 and Urotensin II as cardiovascular peptides in humans are already well established7,8.

Recently, evidence has accumulated indicating that ET-1, Urotensin II and their receptors are expressed in various kinds of tumor cells. Urotensin II was reported to stimulate cell growth of adrenal tumors and neuroblastomas suggesting the possibility that Urotensin II may act as a growth stimulator in tumors8-10. Overexpression of ET-1 and ETAR was reported in different malignancies including prostate cancer, breast and ovarian carcinomas, and human Kaposi’s sarcoma11-16. Hypermethylation of the ETBR correlated with transcriptional downregulation. Reduced expression of ETB receptor was observed in several prostate, bladder and colon cancer cell lines3.

Currently there is increasing evidence that ET-1 may modulate mitogenesis, apoptosis, angiogenesis, tumor invasion and the development of metastases3.

In breast carcinomas it has been demonstrated that overexpression of ET-1 and ETA receptor correlated with parameters that characterize aggressive types of breast cancer15 suggesting that analysis of ETAR expression might be used as a diagnostic marker for evaluating the progression of the disease and effectiveness of treatment. These and other findings have made ET receptors, and especially ETAR, promising therapeutic targets for pharmacological intervention.

Alomone Labs offers polyclonal antibodies to ETAR (#AER-001), ETBR (#AER-002) and UTIIR (#AER-003) that can be used as research tools for exploring the role of endothelins and Urotensin-II in cancer and other pathologies.

References
1. Davenport, A.P. (2002) Pharmacol. Rev. 54, 219.
2. Boivin, B. et al. (2003) J. Biol.Chem. 278, 29153.
3. Grant, K. et al. (2003) Br. J. Cancer. 88, 163.
4. Maguire, J.J. et al. (2000) Br. J. Pharmacol. 131, 441.
5. Matsushita, M. et al. (2001) J. Hypertens. 19, 2185.
6. Maguire, J.J. and Davenport, A.P. (2002) Br. J. Pharmacol. 137, 579.
7. Yanagisawa, M. et al. (1988) Nature 332, 411.
8. Takahashi, K. et al. (2000) Clin. Sci. 103, 35S.
9. Takahashi, K. et al. (2001) Peptides 22, 1175.
10. Takahashi, K. et al. (2003) Peptides 24, 301.
11. Asham, E. et al. (2001) Br. J. Cancer. 85, 1759.
12. Kopetz, E.S. et al. (2002) Invest. New Drugs. 20, 173.
13. Rosano, L. et al. (2003) Am. J. Pathol. 163, 753.
14. Rosano, L. et al. (2003) Cancer Res. 63, 2447.
15. Wulfing, P. et al. (2003) Clin. Cancer Res. 9, 4125.
16. Nelson, J.B. (2003) J. Urol. 170, S65.