Although many people believe that a suntan imparts a healthy glow, the truth is that tanning irreversibly damages the skin and can lead to skin cancer. Researchers from Massachusetts General Hospital have now shown that, in mice at least, inhibiting one of the phosphodiesterases, PDE-4D3, can activate the tanning process without exposure to harmful ultraviolet irradiation.
Using transgenic mice with melanocytes in their epidermis (which normal mice do not have), the group had already shown that inducing cyclic AMP production led to significant pigmentation. Further detailed analysis of the melanin expression pathway identified PDE-4D3 as the key regulator of cyclic AMP activity in melanocytes. Topical treatment of the transgenic mice with a PDE-4 inhibitor (rolipram or Ro 20-1724) for five days caused the skin to darken appreciably and the effect could be further enhanced by co-application of forskolin, which stimulates adenylate cyclase activity.
Although PDE4 isoforms play a key role in regulating intracellular cyclic AMP levels in a variety of tissues, the researchers believe that topical application of a selective PDE-4D3 inhibitor has potential to provide safe tanning and reduce the incidence of skin cancer.
Transient Receptor Potential (TRP) ion channels are a large superfamily of transmembrane proteins which, amongst other functions, help an organism to sense its environment. The TRPV1 channel –which is activated by heat and also by capsaicin, the pungent component of hot chilli peppers – has been linked to the development of epithelial cancers.
A new study by researchers at the University of Michigan and Children’s Hospital Boston shows that the TRPV3 receptor – a molecular sensor for warm temperatures – plays a key role in maintenance of the skin barrier and hair growth and could perhaps also be linked to the development of skin cancer. Epidermal growth factor receptor (EGFR) and one of its ligands, transforming growth factor-α (TGF-α), were known to regulate skin and hair growth and the new study shows that TRPV3 is a key component of the EGFR signalling pathway. Activation of TRPV3 was found to lead to release of TGF-α, which activates EGFR. Activation of EGFR, in turn, increases TRPV3 channel activity, forming a positive feedback loop. Like animals with naturally occurring loss-of-function mutations in the genes for EGFR or TGF-α, TRPV3 knockout mice were found to have curly coats and whiskers.
In the TRPV3 knockout mice, the outer layer of the skin was found to be thinner than normal and to have a dry scaly texture which resulted from impaired terminal differentiation of keratinocytes. The study suggests that small molecule activators of TRPV-3 could be used to treat a variety of skin injuries and diseases such as burns, bed sores, eczema, psoriasis, itch, and fungal infections.
One cautionary note is that mice with overactive EGFR or TGF-α are hairless and develop skin cancers. Upregulation of EGFR has also been linked to a number of human cancers and drugs targeting EGFR are an expanding class of cancer treatments. Although mice overexpressing TRPV3 have not been shown to have an increased number of tumours, this is something that would need to be investigated further. The study is published in the journal Cell.