Selective COX-2 inhibitors modulate cellular senescence in human dermal fibroblasts in a catalytic activity-independent manner

• Published in: Mechanisms of ageing and development 2008-12, Vol.129 (12), p.706-713
• Main Authors: Kim, So Ra, Park, Jung Hae, Lee, Mi Eun, Park, Jeong Soo, Park, Sang Chul, Han, Jeong A.
• Format: Article
• Language: English
• Subjects: Aspirin - pharmacology; Biological and medical sciences; Caveolin 1 - metabolism; Caveolin-1; Celecoxib; Cells, Cultured; Cellular Senescence - drug effects; Cellular Senescence - physiology; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - pharmacology; Cyclooxygenase Inhibitors - pharmacology; Cyclooxygenase-2; Development. Metamorphosis. Moult. Ageing; Fibroblast; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Flurbiprofen - pharmacology; Fundamental and applied biological sciences. Psychology; Humans; Ibuprofen - pharmacology; Inhibitor; Kinetics; Models, Biological; NF-kappa B - metabolism; Nitrobenzenes - pharmacology; Pyrazoles - pharmacology; Reactive Oxygen Species - metabolism; Senescence; Skin - cytology; Skin - drug effects; Skin - metabolism; Skin Aging - drug effects; Skin Aging - physiology; Sulfonamides - pharmacology; Tumor Suppressor Protein p53 - metabolism; Vertebrates: anatomy and physiology, studies on body, several organs or systems
• ISSN: 0047-6374; 1872-6216
• DOI: 10.1016/j.mad.2008.09.003

It has been recently proposed that pro-inflammatory genes such as cyclooxygenase-2 (COX-2) play a key role in the aging process. However, it remains unclear whether the pro-inflammatory activity of COX-2 is involved in the aging process and whether COX-2 inhibitors prevent aging. We therefore examined the effect of COX-2 inhibitors on aging in the cellular senescence model of human dermal fibroblasts (HDFs). While the catalytic activity of COX-2 was observed to increase in the senescence process, we found that among three selective COX-2 inhibitors studied, only NS-398 inhibited the senescence whereas celecoxib and nimesulide accelerated the senescence. Non-selective COX inhibitors including aspirin, ibuprofen and flurbiprofen accelerated the senescence. The senescence-regulating effect of selective COX-2 inhibitors had no correlation with cellular reactive oxygen species levels, NF-κB activities or protein levels of p53 and p21. We instead found that selective COX-2 inhibitors regulate caveolin-1 expression at transcriptional levels, which was closely associated with the inhibitors’ effect on the senescence. Collectively, these results suggest that COX-2 catalytic activity does not mediate HDF senescence and that selective COX-2 inhibitors modulate HDF senescence by a catalytic activity-independent mechanism.