Infrared‐A Irradiation‐induced Inhibition of Human Keratinocyte Proliferation and Potential Mechanisms

• Published in: Photochemistry and photobiology 2020-09, Vol.96 (5), p.1105-1115
• Main Authors: Shimizu, Syota, Aoki, Akihiro, Takahashi, Takuya, Harano, Fumiki
• Format: Article
• Language: English
• Subjects: Aging; AKT protein; Cell cycle; Cell proliferation; Cell Proliferation - radiation effects; Cells, Cultured; Deactivation; Dephosphorylation; Dermis; Epidermis; Exposure; Humans; I.R. radiation; Inactivation; Infrared Rays; Irradiation; Keratinocytes; Keratinocytes - cytology; Keratinocytes - radiation effects; Mechanistic Target of Rapamycin Complex 1 - antagonists & inhibitors; Molecular modelling; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Rapamycin; Reduction; Skin; Skin - pathology; Skin - radiation effects; Skin Aging; Solar radiation; TOR protein
• ISSN: 0031-8655; 1751-1097
• DOI: 10.1111/php.13248

Infrared‐A (IRA), which can penetrate deeply into the human skin, is a major component of solar radiation and is recognized to promote photoaging of human dermis. To our knowledge, however, the cellular and molecular consequences of human epidermis exposure to IRA have not been clarified. Thus, we investigated whether IRA inhibits the proliferation of normal human epidermal keratinocytes (NHEKs). IRA irradiation ed in cell cycle arrest at G1 and a dose‐dependent reduction in the proliferation of NHEKs. We found that mechanistic target of rapamycin complex 1 (mTORC1) was initially inactivated during IRA irradiation due to the formation of stress granules (SGs), and this inactivation was maintained for at least 6 h after irradiation due to Akt dephosphorylation. Furthermore, repeated exposure of human skin equivalents to IRA led to marked thinning of the epidermal cell layer. In conclusion, IRA irradiation inhibits mTORC1 activity possibly through two molecular mechanisms involving SG formation in the early‐phase and subsequent Akt dephosphorylation. This sequential mechanism seems to cause G1 cell cycle arrest and a reduction in cell proliferation, supporting the hypothesis that the decreased proliferation of basal keratinocytes that occurs during skin aging might be partly attributable to IRA radiation. IRA radiation is known to cause dermal photoaging in human skin; however, the cellular and molecular effects in human epidermis resulting from IRA exposure have not been clarified. This study demonstrates that IRA inhibits the activity of mTOR complex 1 (mTORC1) in human epidermal keratinocytes and thereby inhibits cell proliferation. We propose that mTORC1 inactivation caused by IRA irradiation proceeds through a sequential mechanism consisting of the early formation of SGs, followed by sustained dephosphorylation of Akt, leading to cell cycle arrest at G1 and a subsequent reduction of cell proliferation.