Pain Target Linked to Cancer

Blockade of the transient receptor potential vanilloid channel, TRPV1, which is widely expressed in both central and peripheral nervous tissue, has been considered by many groups to be an attractive approach to pain relief. The receptor is activated by a number of endogenous and exogenous stimuli including the endocannabinoid, anandamide; capsaicin, the ‘hot’ component of chilli peppers; low pH; and heat. The sensitivity of TRPV1 to heat has suggested a role in maintenance of body temperature, and clinical trials of at least one TRPV1 antagonist were stopped because of unacceptable levels of hyperthermia.

A new study published in the January 19^th Online First edition of the journal Cancer Research now suggests a link between TRPV1 and the development of cancer. The authors show that TRPV1 interacts with epidermal growth factor receptor (EGFR), a receptor tyrosine kinase that is overexpressed in many human epithelial cancers. Interaction of TRPV1 with EGFR was found to recruit the ubiquitin ligase, Cbl, leading to ubiquitylation and lysosomal degradation of EGFR.

In a further set of experiments, the authors showed that mouse epidermal cells over-expressing TRPV1 were significantly less likely to undergo malignant transformation when stimulated with EGFR, either with or without a tumour promoter. TRPV1 was next shown to be expressed in the skin of wild type mice but not TRPV1 knock-out mice; the knock-out mice also had elevated levels of EGFR protein in the skin. When exposed to the tumour initiator, 7,12-dimethylbenz[a]anthracene (DMBA) and the promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), almost all TRPV1 knock-out mice developed larger and more numerous tumours than age- and sex-matched wild type animals. Pretreatment of all mice with the EGFR antagonist, AG1478, significantly suppressed tumour formation, but the effect was much greater in the TRPV1 knock-out animals.

The authors suggest that channels such as TRPV1 are able have a direct effect which is independent of their function as ion channels; the TRP family of proteins seems to show different levels of expression in cancer tissues, although whether these changes are cause or effect is not known.