Mitomycin C induces apoptosis via Fas/FasL dependent pathway and suppression of IL-18 in cervical carcinoma cells.
Mitomycin C (MMC) is used fairly widely as an anticancer drug, as it possesses mechanisms of action which are preferable to other chemotherapeutic compounds, including cisplatin, docetaxel, and lovastatin. In the previous study, we established the RSV-luc promoter analysis system, which is used to screen drugs against cervical carcinomas caused by HPV infection. We then demonstrated the repression of HPV E6-activated RSV promoter activity by anticancer agents such as carboplatin (CA), cisplatin (CIS), and MMC. In these studies, we focused on the investigation of apoptotic mechanisms in MMC-treated cervical carcinoma cell lines, most notably SiHa/pRSV-luc (KCTC 0427BP) and SiHa. DNA fragmentation assays and TUNEL staining revealed that MMC and CIS, but not CA, resulted in apoptosis. MMC treatment induced a reduction in the expressions of the E6 oncogene and IL-18, in a p53-independent manner. MMC also increased FasL expression and induced the processing of caspases-8 and -3. Our results indicated that MMC induced apoptosis in SiHa/pRSV-luc and SiHa cells via caspase-8 and -3 processing, in a Fas/FasL-dependent manner. MMC also suppressed the expression of IL-18 in the same cells. MMC also down-regulated IkappaB expression, and up-regulated p65 expression. These results suggest that MMC induces apoptosis, not only through caspase-8 and -3 dependent Fas/FasL pathway, but also via the regulation of NF-kappaB activity and IL-18 expression.
Kang
Yun Hee
YH
Division of Cellomics, Laboratory of Cell Biology, Korea Research Institute of Bioscience and Biotechnology, P.O. Box 115, Daejeon 305-600, South Korea.
Lee
Kyung-Ae
KA
Ryu
Chun Jeih
CJ
Lee
Hee-Gu
HG
Lim
Jong-Seok
JS
Park
Sue Nie
SN
Paik
Sang-Gi
SG
Yoon
Do-Young
DY
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D016685:Mitomycin / Q000494:pharmacology*; D009856:Oncogene Proteins, Viral / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection; D048069:Tumor Necrosis Factors / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms; D019014:fas Receptor
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; C068651:E6 protein, Human papillomavirus type 16; C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D020672:I-kappa B Proteins; D020382:Interleukin-18; D008562:Membrane Glycoproteins; D009856:Oncogene Proteins, Viral; D018124:Receptors, Tumor Necrosis Factor; D012097:Repressor Proteins; D048069:Tumor Necrosis Factors; D019014:fas Receptor; D016685:Mitomycin; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases; D002945:Cisplatin