Endothelins and their receptors in cancer: identification of therapeutic targets

Abstract

Endothelins and their receptors are important in normal physiology, but have been implicated in various pathophysiological conditions. Members of the so-called "endothelin axis" are dysregulated in a wide range of human cancers, opening the door for novel anticancer therapies. Established cancer chemotherapeutic agents and drugs that target specific components of the endothelin axis have been combined with promising results, but more work is needed in this area. The endothelin axis affects numerous signaling pathways, including Ras, mitogen activated protein kinases, β-catenin/T-cell factor/lymphoid enhancer factor, nuclear factor-κB (NFκB), SNAIL, and mammalian target of rapamycin (mTOR). There is much still to learn about optimizing drug specificity in this area, while minimizing off-target effects. Selective agonists and antagonists of endothelins, their receptors, and upstream processing enzymes, as well as knockdown strategies in vitro, are providing valuable leads for testing in the clinical setting. The endothelin axis continues to be an attractive avenue of scientific endeavor, both in the cancer arena and in other important health-related disciplines.

Figure 1. Endothelins, their receptors, and downstream signaling pathways

Figure modified from previous schemes [1,8,10,19], with updates as indicated in the text. For abbreviations see text and [8]. Examples are shown at the top of the figure of cancer therapeutic/chemopreventive agents that have been examined for their effects on the endothelin axis. The figure is over-simplified and does not detail the full extent of cross-talk among the various intracellular signaling pathways. Nor does it accurately reflect the complete range of actions for the inhibitors shown. For example, EGCG acts on Met and other tyrosine kinases, as well as on downstream components of NFκB and β-catenin/T-cell factor/lymphoid enhancer (β-cat/Tcf/Lef) factor signaling.