AKT status controls susceptibility of malignant keratinocytes to the early-activated and UVB-induced apoptotic pathway.
In previous work, we have described an early-activated and ultraviolet B (UVB)-induced apoptotic pathway in human keratinocytes, which can be completely inhibited by AKT activation. We now compared this response of primary human keratinocytes with the response of two p53-mutated squamous cell carcinoma (SCC)-derived cell lines (A431 and A253) to an apoptotic UVB dose. In these cell lines, both the basal AKT phosphorylation status and the apoptotic response to UVB diverged strongly from the response of healthy primary keratinocytes. Even more, a remarkable correlation was found between the two. Although a constitutive dual phosphorylation of AKT rendered the A253 SCC cell line completely resistant to the early-activated and UVB-induced apoptotic pathway, deficient T308 phosphorylation of AKT in the SCC cell line A431 led to a greatly augmented sensitivity to the early-activated, UVB-induced apoptotic pathway. These results indicate that the preservation of a healthy AKT pathway is essential for a wild-type UVB-induced apoptotic response in skin, and suggest that AKT-mediated dysregulation of the early-activated apoptotic response to UVB is an important event in the oncogenic transformation of keratinocytes.
Decraene
David
D
Department of Dermatology, Faculty of Medicine, Katholieke Universiteit Leuven, Belgium. david.decraene@med.kuleuven.ac.be
Van Laethem
An
A
Agostinis
Patrizia
P
De Peuter
Lucie
L
Degreef
Hugo
H
Bouillon
Roger
R
Garmyn
Marjan
M
D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell; D045744:Cell Line, Tumor / Q000166:cytology / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D002648:Child; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012878:Skin Neoplasms; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects; D000077191:Wortmannin
D000730:Androstadienes; D010726:Phosphodiesterase Inhibitors; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin