Inhibition of Mammalian Target of Rapamycin (mTOR) in Epidermis
Cutaneous squamous cell carcinoma (cSCC) is one of the most common Caucasian skin cancers and is particularly prevalent following chronic ultraviolet (UV) radiation exposure and in immunosuppressed patients. Recent use of rapamycin as an immunosuppressant significantly reduces SCC after organ transplantation. However the mechanism remains unclear. Rapamycin inhibits mammalian target of rapamycin (mTOR) kinase, downstream from phosphatidylinositol-3 kinase (PI3K) and Akt kinases previously implicated in SCC. The aim was to find the effects of rapamycin on PI3K-Akt-mTOR signalling in epidermis in order to understand rapamycin’s tumour suppressing activity in skin. Rapamycin increases epidermal Akt phosphorylation via inhibition of an mTOR complex 1 (mTORC1)-dependent negative feedback loop to insulin receptor substrate-1. In a skin experimental model, rapamycin selectively increases phosphorylation of Akt1, the epidermal Akt isoform down-regulated in SCC and also down-regulated by UV. Epidermal Akt2, up-regulated in tumours and by UV, is unaffected. Rapamycin enhances restoration of Akt1 phosphorylation in skin recovering from UV radiation, suggesting a mechanism for rapamycin’s anti-tumour activity in epidermis in spite of its efficient immunosuppressive properties. As rapamycin targets mTORC1, newer classes of mTOR inhibitors active against mTORC1 and mTORC2 are under development. While comparing the two drug classes it was found that rapamycin unexpectedly increases epidermal mTORC2 activity. Since mTORC2 signalling influences lipid synthesis and epidermis requires extensive lipogenesis for formation of its protective barrier, the relationship between epidermal mTORC2 signalling, lipogenesis and barrier to UV was explored. Rapamycin increased epidermal lipid levels, but this increase was not sufficient to protect against UV-induced DNA damage. 3 In conclusion, rapamycin treatment can increase PI3K/Akt1 and mTORC2 signalling and lipid levels in epidermis. Rapamycin can increase epidermal Akt1 phosphorylation during UV recovery, which may contribute to the anti-cancer action of rapamycin in skin. Rapamycin’s potential to increase epidermal lipid levels makes it an interesting possible therapeutic for treating skin disorders with dyslipidemia.
AuthorsSully, Katherine L
- Theses