Down-regulation of p21Waf-1 protein facilitates IR- and UV-induced apoptosis in human squamous carcinoma cells.
DNA damage via radiation exposure and administration of chemotherapeutic agents induce apoptosis, which is a basic mechanism for non-surgical anti-cancer treatment. We analyzed ionizing radiation (IR)- or ultraviolet (UV)-induced apoptosis in human laryngeal carcinoma (HEp-2) and uterine cervical carcinoma (HeLa) cells, and found that HeLa cells were significantly more sensitive to both IR- and UV-induced apoptosis compared to HEp-2 cells, in spite of the same histological type and p53 status. The cyclin-dependent kinase (Cdk) inhibitor, p21Waf-1 was modified differently between the two cancer cell types, whereas p53 protein was induced in a similar manner after IR or UV treatment. IR steadily induced p21Waf-1 protein in HEp-2 cells, but not in HeLa cells. Additionally, p21Waf-1 protein recovered close to the basal level only in HEp-2 cells, although UV caused rapid, dramatic and caspase-independent reduction of p21Waf-1 protein in both cancer cells. Furthermore, overexpression of p21Waf-1 protein in these cells by transient transfection and in stable cell lines in a tetracycline-regulated system, rescued IR- and UV-induced apoptosis. Finally, suppression of p21Waf-1 protein using antisense oligodeoxynucleotide transfection facilitated UV-induced apoptosis in both HEp-2 and HeLa cells. We concluded that p21Waf-1 protein is modified independently of p53 and functions as an inhibitor of IR- as well as UV-induced apoptosis in squamous carcinoma cells.
Izumaru
Shinsuke
S
Department of Otolaryngology-Head and Neck Surgery, Kurume University, School of Medicine, Kurume, Japan.
Arima
Nobuyuki
N
Toyozumi
Yasuo
Y
Kato
Seiya
S
Morimatsu
Minoru
M
Nakashima
Tadashi
T
D017209:Apoptosis / Q000528:radiation effects*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005720:Gamma Rays; D006367:HeLa Cells; D006801:Humans; D007822:Laryngeal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000528:radiation effects; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D020320:Oligoribonucleotides, Antisense; D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; D020169:Caspases