{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T05:50:14Z","timestamp":1761630614960},"reference-count":52,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2012,6,20]],"date-time":"2012-06-20T00:00:00Z","timestamp":1340150400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Experimental Dermatology"],"published-print":{"date-parts":[[2012,7]]},"abstract":"Abstract<\/jats:title>Actinic keratosis (AK<\/jats:styled-content>) is characterized by high prevalence and the risk to proceed to squamous cell carcinoma (SCC<\/jats:styled-content>). Cyclooxygenase\u20102 (COX<\/jats:styled-content>\u20102)\u2010mediated prostaglandin E<\/jats:styled-content>2 (PGE<\/jats:styled-content>\n2<\/jats:sub>) synthesis has been reported in AK<\/jats:styled-content> and SCC<\/jats:styled-content>, and the COX<\/jats:styled-content> inhibitor diclofenac in hyaluronic acid (diclofenac\/HA<\/jats:styled-content>) was approved for AK<\/jats:styled-content> therapy. Its mode of action, however, remained to be unravelled. In the present study, diclofenac resulted in reduced PGE<\/jats:styled-content>\n2<\/jats:sub> levels in apoptosis\u2010sensitive cutaneous SCC<\/jats:styled-content> cell lines (SCL<\/jats:styled-content>\u2010II<\/jats:styled-content>, SCC<\/jats:styled-content>\u201012, SCC<\/jats:styled-content>\u201013) whereas no PGE<\/jats:styled-content>\n2<\/jats:sub> and no COX<\/jats:styled-content>\u20102 expression was detectable in a SCC<\/jats:styled-content> cell line resistant to apoptosis induction (SCL<\/jats:styled-content>\u2010I<\/jats:styled-content>). Activation of mitochondrial apoptosis pathways was evident in SCC<\/jats:styled-content> cells owing to loss of the mitochondrial membrane potential and release of the mitochondrial factors cytochrome c<\/jats:italic> and apoptosis\u2010inducing factor. Characteristic proapoptotic changes at the level of B<\/jats:styled-content>cl\u20102 proteins occurred in sensitive cells, as upregulation of B<\/jats:styled-content>ad and downregulation of M<\/jats:styled-content>cl\u20101 and B<\/jats:styled-content>cl\u2010w. In contrast, Bad was already high, and M<\/jats:styled-content>cl\u20101 and B<\/jats:styled-content>cl\u2010w were already low in resistant SCL<\/jats:styled-content>\u2010I<\/jats:styled-content>, even without treatment, which may be explained by the lack of PGE<\/jats:styled-content>\n2<\/jats:sub>. An antiapoptotic downregulation of proapoptotic B<\/jats:styled-content>cl\u20102 proteins Noxa and Puma was, however, also seen in SCL<\/jats:styled-content>\u2010I<\/jats:styled-content>, suggesting here pathways independent of COX<\/jats:styled-content>\u20102. The regulations of M<\/jats:styled-content>cl\u20101 and B<\/jats:styled-content>ad were also reproduced in SCC<\/jats:styled-content> cells by the more selective COX<\/jats:styled-content>\u20102 inhibitor celecoxib, thus further underlining the specific role of COX<\/jats:styled-content>\u20102. The findings illuminate the mode of action of diclofenac\/HA<\/jats:styled-content> in SCC<\/jats:styled-content> cells as well as principles of their resistance, which may allow further adaptation and improvement of the new therapy.<\/jats:p>","DOI":"10.1111\/j.1600-0625.2012.01516.x","type":"journal-article","created":{"date-parts":[[2012,4,30]],"date-time":"2012-04-30T06:28:33Z","timestamp":1335767313000},"page":"520-525","source":"Crossref","is-referenced-by-count":12,"title":["Activation of mitochondrial apoptosis pathways in cutaneous squamous cell carcinoma cells by diclofenac\/hyaluronic acid is related to upregulation of Bad as well as downregulation of Mcl\u20101 and Bcl\u2010w"],"prefix":"10.1111","volume":"21","author":[{"given":"Paul M.","family":"Rodust","sequence":"first","affiliation":[{"name":"Department of Dermatology and Allergy Skin Cancer Center University Medical Center Charit\u00e9 Berlin 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