The mTOR-inhibitor Sirolimus decreases the cyclosporine-induced expression of the oncogene ATF3 in human keratinocytes

Publication date: Available online 5 September 2018

Source: Journal of Dermatological Science

Author(s): Katrin Schaper-Gerhardt, Antje Walter, Christina Schmitz-Rode, Imke Satzger, Ralf Gutzmer

Abstract

Background

Due to their immunosuppressive therapy, organ transplant recipients (OTRs) exhibit a high incidence for the development of cutaneous squamous cell carcinoma (cSCC). Randomized studies of kidney-transplanted patients indicate a significant lower susceptibility for cSCC among patients receiving the mTOR-inhibitor Sirolimus, compared to patients without mTOR-regimen. The exact mechanism, how mTOR inhibition affects keratinocyte carcinogenesis remains unclear.

Objective

Our aim was to investigate the impact of Sirolimus on the expression level of the oncogene ATF3, which is involved in the development and progression of cSCC.

Methods

We incubated human keratinocytes, cSSC cell lines and 3D skin equivalents with Sirolimus, exposed the cells to calcineurin inhibitors (CNI) and UVA-radiation and measured the expression level of ATF3 by real-time PCR and western blot.

Results

We show that Sirolimus downregulates the expression of ATF3 induced by cyclosporine or cyclosporine plus UV-radiation in keratinocytes. In line with this we demonstrate a decrease in ATF3 expression, by incubating 3D skin equivalents with Sirolimus prior to cyclosporine and UV-light. However, Sirolimus has no significant impact on the ATF3 expression levels of cyclosporine stimulated cSCC cell lines.

Conclusion

Taken together, our study demonstrates that Sirolimus downregulates the CNI or UV-induced ATF3 expression in human keratinocytes, which could be a potential molecular mechanism how Sirolimus reduces cSCC in OTRs. The lack of ATF3 suppression by Sirolimus in cSCC cell lines fits to observations from clinical studies which demonstrated a clinical benefit from the switch to an mTOR-regimen in patients with low tumor burden in early stage of disease.

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