UV-induced squamous cell carcinoma--a role for antiapoptotic signalling pathways.
The incidence of nonmelanoma skin cancer including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) has dramatically increased in the last decades, and chronic sun exposure was identified as a main etiologic agent. UV radiation may produce DNA damage either directly or through reactive oxygen species (ROS). As mutations caused by UV may lead to skin cancer due to oncogene activation and tumor suppressor gene inactivation, efficient safeguard mechanisms have been developed during evolution. These enclose induction of apoptosis and formation sunburn cells aiming at the removal of premalignant cells. The keratinocyte apoptotic machinery in response to UV consists of both intrinsic/mitochondrial and extrinsic/death receptor-mediated cell-death pathways, which are particularly regulated by mitogen-activated protein kinases (MAPKs, JNK and p38) and the tumor-suppressor protein p53. For development of skin cancer, it appears that critical steps in apoptosis control are dysregulated leading to resistance both to death ligand-mediated and intrinsic proapoptotic pathways. These particularly include inactivation of p53, as well as activation of EGFR, COX-2 and MAPKs, which result in specific regulation of Bcl-2 proteins, death ligands and death receptors. The final unravelling of apoptosis regulation in epithelial skin cancer may allow the development of new targeted therapeutic strategies.
Rodust
P M
PM
Charité-Universitätsmedizin Berlin, Department of Dermatology and Allergy, HTCC Skin Cancer Center Charité, 10117 Berlin, Germany.
Stockfleth
E
E
Ulrich
C
C
Leverkus
M
M
Eberle
J
J
D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D002280:Basal Cell Carcinoma / Q000209:etiology / Q000235:genetics / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D004249:DNA Damage / Q000235:genetics; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000473:pathology / Q000528:radiation effects; D009381:Neoplasms, Radiation-Induced / Q000209:etiology / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000528:radiation effects*; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*
D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human