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The mTOR-inhibitor Sirolimus decreases the cyclosporine-induced expression of the oncogene ATF3 in human keratinocytes.
- Source :
-
Journal of dermatological science [J Dermatol Sci] 2018 Nov; Vol. 92 (2), pp. 172-180. Date of Electronic Publication: 2018 Sep 05. - Publication Year :
- 2018
-
Abstract
- Background: Due to their immunosuppressive therapy, organtransplant 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.<br />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.<br />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.<br />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.<br />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 a mTOR-regimen in patients with low tumor burden in early stage of disease.<br /> (Copyright © 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Carcinogenesis chemically induced
Carcinogenesis radiation effects
Carcinoma, Squamous Cell etiology
Carcinoma, Squamous Cell pathology
Carcinoma, Squamous Cell prevention & control
Cell Culture Techniques
Cell Line, Tumor
Down-Regulation
Humans
Immunosuppressive Agents adverse effects
Keratinocytes metabolism
Keratinocytes pathology
Keratinocytes radiation effects
Oncogenes
Organ Transplantation adverse effects
Sirolimus therapeutic use
Skin cytology
Skin drug effects
Skin pathology
Skin radiation effects
Skin Neoplasms etiology
Skin Neoplasms pathology
Skin Neoplasms prevention & control
TOR Serine-Threonine Kinases antagonists & inhibitors
Ultraviolet Rays adverse effects
Activating Transcription Factor 3 metabolism
Calcineurin Inhibitors adverse effects
Cyclosporine adverse effects
Keratinocytes drug effects
Sirolimus pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1873-569X
- Volume :
- 92
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of dermatological science
- Publication Type :
- Academic Journal
- Accession number :
- 30220530
- Full Text :
- https://doi.org/10.1016/j.jdermsci.2018.08.013