Inhibition of apoptosis facilitates necrosis induced by cisplatin in gastric cancer cells.
Although cisplatin has been shown to induce both apoptosis and necrosis in cancer cells, the potential interconnections between these modes of cell death induced by the drug remain unknown. We studied this phenomenon in gastric cancer cell lines and identified one cell line (SGC-7901) that underwent apoptosis, and another cell line (BGC-823) that primarily underwent nonapoptotic cell death, in response to cisplatin. Apoptosis in cisplatin-treated SGC-7901 cells seemed to be caspase dependent and was mediated, at least in part, by the BH3-only protein, Noxa. This was evidenced by the rapid upregulation of Noxa and inhibition of apoptosis by small interfering RNA knockdown of Noxa. Nonapoptotic cell death induced by cisplatin in BGC-823 cells was characterized by lack of DNA fragmentation, delayed externalization of phosphatidylserine, caspase independence, plasma membrane disruption, and intracellular vacuole formation, indicative of necrosis. Surprisingly, blockage of apoptosis induction by a general caspase inhibitor or by Noxa small interfering RNA in SGC-7901 failed to protect against cisplatin-induced cell death. Under such conditions, SGC-7901 cells displayed cellular features associated with necrosis. Cisplatin-induced apoptosis, thus, seems to precede necrosis when the apoptotic machinery is operative. When the apoptosis program is defective, necrotic cell death takes place as an alternative pathway leading to cell demise. Induction of different modes of cell death that are interrelated in the same cells by cisplatin has the potential to be exploited in formulating new adjuvant cancer therapies.
Zhang
Lin Jie
LJ
Department of Immunology, The Anhui Medical University, Hefei, China.
Hao
Yuan Zhang
YZ
Hu
Chun Song
CS
Ye
Yan
Y
Xie
Qi Peng
QP
Thorne
Rick F
RF
Hersey
Peter
P
Zhang
Xu Dong
XD
D000255:Adenosine Triphosphate / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002084:Butylated Hydroxytoluene / Q000031:analogs & derivatives / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D009336:Necrosis / Q000139:chemically induced; D010718:Phosphatidylserines / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D014162:Transfection
D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C498702:PMAIP1 protein, human; D010718:Phosphatidylserines; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D002084:Butylated Hydroxytoluene; C006008:BH 3; D000255:Adenosine Triphosphate; D053148:Caspase 3; D020169:Caspases; D002945:Cisplatin