Up-regulation of FLIP in cisplatin-selected HeLa cells causes cross-resistance to CD95/Fas death signalling.
Cisplatin-selected cervix carcinoma HeLa cell lines induced less apoptosis, and weaker activation by cisplatin or Fas-activating antibody, of mitochondrial-associated caspase-9 and death receptor-mediated caspase-8 than did parental cells. Furthermore, less DISC (death-inducing signalling complex) was formed in cisplatin-selected cell lines than in parental cells. Ac-IETD-CHO (acetyl-Ile-Glu-Thr-Asp-aldehyde), which has a certain preference for inhibiting caspase-8, or Fas-antagonistic antibody, significantly inhibited cisplatin-induced apoptosis in both parental and cisplatin-selected HeLa cell lines. These results imply that cell-surface death signalling is inducible by cisplatin; that reduction of this pathway is associated with drug resistance, and that cisplatin-selected cells acquire cross-resistance to cell-surface death signalling. Sequential up-regulation of FLIP (FLICE-like inhibitory protein), but not Bcl-2, Bcl-x(L) or inhibitors of apoptosis protein (IAPs), was observed in resistant cells but not in parental cells. The inhibition of FLIP by FLIP antisense oligonucleotides promotes cisplatin and Fas-antibody-induced apoptosis. However, the modulation of apoptosis by FLIP antisense oligonucleotides in resistant cells is greater than that in parental cells. The presented data reveal that the up-regulation of FLIP may contribute to the suppression of apoptosis and thereby change cells that are resistant to cisplatin and Fas-mediated death signals. The results also show that cancer cells that have undergone long-term chemotherapy and become chemoresistant may change the FLIP level, becoming cross-resistant to death factors such as Fas.
Kamarajan
Pachiyappan
P
Tumor Biology Laboratory, Department of Biochemistry, Chang Gung University, Taoyuan, Taiwan 333, Republic of China.
Sun
Nian-Kang
NK
Chao
Chuck C-K
CC
D000906:Antibodies / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015398:Signal Transduction; D015854:Up-Regulation; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019014:fas Receptor; D020169:Caspases; D002945:Cisplatin