Up-regulation of FLIP in cisplatin-selected HeLa cells causes cross-resistance to CD95/Fas death signalling

Biochem J. 2003 Nov 15;376(Pt 1):253-60. doi: 10.1042/BJ20030659.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies / pharmacology
  • Antineoplastic Agents / antagonists & inhibitors
  • Antineoplastic Agents / pharmacology*
  • Apoptosis*
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / metabolism*
  • Caspases / metabolism
  • Cisplatin / antagonists & inhibitors
  • Cisplatin / pharmacology*
  • Drug Resistance, Neoplasm
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Signal Transduction
  • Up-Regulation
  • fas Receptor / immunology
  • fas Receptor / metabolism*


  • Antibodies
  • Antineoplastic Agents
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • fas Receptor
  • Caspases
  • Cisplatin