Cisplatin induces apoptosis in oral squamous carcinoma cells by the mitochondria-mediated but not the NF-kappaB-suppressed pathway.
Cisplatin (CDDP) is a potent DNA-damaging anticancer agent, and its cytotoxic action is exerted by the induction of apoptosis. However, activation of the transcription factor NF-kappaB results in protection against apoptosis. We examined the molecular mechanisms involved in the induction of apoptosis by CDDP as regards both suppression of NF-kappaB and activation of caspases. Human oral squamous carcinoma cells (B88) were employed in this study. We found that CDDP treatment affected neither NF-kappaB activity nor the expression levels of antiapoptotic proteins, including TRAF-1, TRAF-2, and cFLIP, in B88 cells. However, two apoptosome molecules, cytochrome c and Apaf-1, were significantly augmented in the cytoplasm by CDDP treatment. Further, the activation of caspase-9 and caspase-3, downstream molecules leading to mitochondria-mediated apoptosis, were detected after treatment with CDDP. Finally, apoptosis was also clearly observed, as evidenced by cleavage of PARP through the activation of caspase-3. These findings suggest that CDDP exerts its apoptotic action by the mitochondria-mediated activation of caspases but not by the activation of caspases due to the inhibition of NF-kappaB activity that follows the suppression of antiapoptotic proteins.
Azuma
M
M
Second Department of Oral and Maxillofacial Surgery and Oncology, Tokushima University School of Dentistry, 3 Kuramoto-cho, Tokushima 770-8504, Japan. azumasa@dent.tokushima-u.ac.jp
Tamatani
T
T
Ashida
Y
Y
Takashima
R
R
Harada
K
K
Sato
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003574:Cytochrome c Group / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000473:pathology*; D016328:NF-kappa B / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003574:Cytochrome c Group; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D020169:Caspases; D002945:Cisplatin