Premium
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‐1 and Bcl‐w
Author(s) -
Rodust Paul M.,
Fecker Lothar F.,
Stockfleth Eggert,
Eberle Jürgen
Publication year - 2012
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/j.1600-0625.2012.01516.x
Subject(s) - downregulation and upregulation , apoptosis , puma , diclofenac , cancer research , programmed cell death , cyclooxygenase , chemistry , mitochondrion , microbiology and biotechnology , biology , biochemistry , enzyme , gene
Actinic keratosis ( AK ) is characterized by high prevalence and the risk to proceed to squamous cell carcinoma ( SCC ). Cyclooxygenase‐2 ( COX ‐2)‐mediated prostaglandin E 2 ( PGE 2 ) synthesis has been reported in AK and SCC , and the COX inhibitor diclofenac in hyaluronic acid (diclofenac/ HA ) was approved for AK therapy. Its mode of action, however, remained to be unravelled. In the present study, diclofenac resulted in reduced PGE 2 levels in apoptosis‐sensitive cutaneous SCC cell lines ( SCL ‐ II , SCC ‐12, SCC ‐13) whereas no PGE 2 and no COX ‐2 expression was detectable in a SCC cell line resistant to apoptosis induction ( SCL ‐ I ). Activation of mitochondrial apoptosis pathways was evident in SCC cells owing to loss of the mitochondrial membrane potential and release of the mitochondrial factors cytochrome c and apoptosis‐inducing factor. Characteristic proapoptotic changes at the level of B cl‐2 proteins occurred in sensitive cells, as upregulation of B ad and downregulation of M cl‐1 and B cl‐w. In contrast, Bad was already high, and M cl‐1 and B cl‐w were already low in resistant SCL ‐ I , even without treatment, which may be explained by the lack of PGE 2 . An antiapoptotic downregulation of proapoptotic B cl‐2 proteins Noxa and Puma was, however, also seen in SCL ‐ I , suggesting here pathways independent of COX ‐2. The regulations of M cl‐1 and B ad were also reproduced in SCC cells by the more selective COX ‐2 inhibitor celecoxib, thus further underlining the specific role of COX ‐2. The findings illuminate the mode of action of diclofenac/ HA in SCC cells as well as principles of their resistance, which may allow further adaptation and improvement of the new therapy.