FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells

Maria Rita Rippo, Simona Moretti, Silvia Vescovi, Marco Tomasetti, Sara Orecchia, Giuseppe Amici, Alfonso Catalano, Antonio Procopio

Research output: Contribution to journalArticle

Abstract

Tumors have developed several forms of resistance to receptor-induced cell death. Here, we show that malignant mesothelial (MM) cell lines as well as primary MM cells and normal mesothelial (NM) cells express Fas and TNF-related apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5. We found that, although Fas expression levels are comparable, only MM cells are resistant to cell death. Furthermore, MM cells show resistance to TRAIL-induced apoptosis. Caspase-8 (FLICE) is not activated by death receptors triggering in malignant cells whereas it is well activated by nonreceptor stimuli, such as UV radiation. We found that FLIP (FLICE-Inhibitory Protein) is constitutively expressed in all MM cell lines and is more expressed in primary MM cells than in NM cells. Knockdown of FLIP expression in MM cell lines, by a FLIPsiRNA, re-established the normal response to apoptosis induced by Fas or DR4/DR5, which was blocked by pretreatment with the caspase-8 inhibitor z-IETD-fmk. These results indicate that MM cells develop an intrinsic resistance to apoptosis induced by death receptors upregulating the expression of the antiapoptotic protein c-FLIP.

Original languageEnglish
Pages (from-to)7753-7760
Number of pages8
JournalOncogene
Volume23
Issue number47
DOIs
Publication statusPublished - Oct 14 2004

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Keywords

  • Apoptosis
  • Caspase-8
  • Fas
  • FLIP
  • Malignant mesothelioma
  • TRAIL

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Rippo, M. R., Moretti, S., Vescovi, S., Tomasetti, M., Orecchia, S., Amici, G., Catalano, A., & Procopio, A. (2004). FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells. Oncogene, 23(47), 7753-7760. https://doi.org/10.1038/sj.onc.1208051