Radiation-induced cell death is independent of the apoptotic signals mediated by death-associated protein kinase in human cervical squamous cell carcinoma cells.
Death-associated protein kinase (DAPK) was originally identified as a positive mediator of interferon-gamma (IFNgamma)-induced apoptosis in cervical cancer cells, and interferons have been reported to enhance radiosensitivity in various types of squamous cell carcinoma. To examine whether DAPK can regulate cancer cell radiosensitivity, we investigated DAPK expression and radiosensitivity in human cancer cell lines, including the cervical squamous cell carcinoma cell line, ME180, which is both radiosensitive and IFNgamma-sensitive. Of the 5 human cancer cell lines examined, ME180 cells were the most radiosensitive, but their level of DAPK protein expression was undetectable by western blotting. A comparative study of ME180 cells with 2 other uterine cancer cell lines, HHUA and HOKUG, revealed no significant relationships between cellular radiosensitivity and DAPK protein expression or hypermethylation of the DAPK promoter CpG island. INFgamma dose-dependently inhibited ME180 cell proliferation, but did not induce any cell death. IFNgamma significantly enhanced the radiosensitivity of ME180 cells with a slight increase in DAPK protein expression, while irradiation significantly reduced their sensitivity to the growth-inhibitory signals of INFgamma. Analyses of 6 monoclonal cisplatin-resistant subclones established from ME180 cells revealed that all 6 were significantly more radioresistant than the parent ME180 cells without any change in the DAPK protein expression. These results indicate that DAPK does not regulate radiation-induced cell death and that it cannot be either a target molecule for radiotherapy with gene therapy or a prognostic marker for cervical cancer patients treated with radiotherapy.
Tanaka
Tetsuji
T
Department of Obstetrics and Gynecology, Wakayama Medical University, 811-1 Kimi-idera, Wakayama 641-0012, Japan. tetanaka@wakayama-med.ac.jp
Bai
Tao
T
Yukawa
Kazunori
K
Umesaki
Naohiko
N
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D018899:CpG Islands; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases; D004307:Dose-Response Relationship, Radiation; D004587:Electrophoresis, Agar Gel; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D013058:Mass Spectrometry; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011827:Radiation; D011836:Radiation Tolerance; D013447:Sulfites / Q000494:pharmacology; D002583:Uterine Cervical Neoplasms / Q000473:pathology*
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D013447:Sulfites; D007371:Interferon-gamma; D004247:DNA; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002945:Cisplatin