engleski

Endothelin axis and apoptosis

Endothelin axis (endothelin-1, -2 and -3, and endothelin receptors ETAR and ETBR) plays the key role in the various functions of the organism: acts as a modulator of vascular tone, tissue differentiation, growth and development, cell proliferation, and hormone synthesis. In addition to its physiological role, endothelin axis or individual components of the system, can have a significant effect on the tissue remodelling process and tumorigenesis. For example, endothelin-1 modulates mitosis, apoptosis and angiogenesis and can stimulate tumour invasion and metastasis. Increased endothelin-1 expression has been demonstrated in breast, ovarian, prostate and colorectal cancers. In tumour cells, the binding of endothelin-1 to ETA receptor induces signalling pathway for survival. Endothelin-1 triggers the anti-apoptotic signal through phosphatidylinositol 3-kinase (PI3-K)-dependent Akt phosphorylation. Endothelin receptors are coupled with G-proteins and they differ in sensitivity to antagonists. G- proteins are involved in cell signalling via adenylate cyclase, ion channels, PLC, PLA2, PKC, intracellular Ca2+, calcineurin and MAP kinase. It is believed that this activity is mediated by ETAR, since the application of their specific antagonist BQ-123 causes a reverse effect. Endothelin receptor antagonists such as A-127722, BQ-123, BQ-788, etc. act specifically on either proliferation or apoptosis depending on the cell type. Today, certain endothelin receptor antagonists, such as atrasentan, are applied in the treatment of lung and prostate cancer or are at different phases of clinical trials.

Endothelin axis; apoptosis; endothelin receptor antagonists

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