Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells.

T. Wilson, M. McEwan, Kirsty McLaughlin, Christophe Le Clorennec, Wendy Allen, Dean Fennell, Patrick Johnston, Daniel Longley

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Death receptors can directly (type I cells) or indirectly induce apoptosis by activating mitochondrial-regulated apoptosis (type II cells). The level of caspase 8 activation is thought to determine whether a cell is type I or II, with type II cells less efficient at activating this caspase following death receptor activation. FLICE-inhibitory protein (FLIP) blocks death receptor-mediated apoptosis by inhibiting caspase 8 activation; therefore, we assessed whether silencing FLIP could convert type II cells into type I. FLIP silencing-induced caspase 8 activation in Bax wild-type and null HCT116 colorectal cancer cells; however, complete caspase 3 processing and apoptosis were only observed in Bax wild-type cells. Bax-null cells were also more resistant to chemotherapy and tumor necrosis factor-related apoptosis inducing ligand and, unlike the Bax wild-type cells, were not sensitized to these agents by FLIP silencing. Further analyses indicated that release of second mitochondrial activator of caspases from mitochondria and subsequent inhibition of X-linked inhibitor of apoptosis protein (XIAP) was required to induce full caspase 3 processing and apoptosis following FLIP silencing. These results indicate that silencing FLIP does not necessarily bypass the requirement for mitochondrial involvement in type II cells. Furthermore, targeting FLIP and XIAP may represent a therapeutic strategy for the treatment of colorectal tumors with defects in mitochondrial-regulated apoptosis.
Original languageEnglish
Pages (from-to)63-72
Number of pages10
JournalOncogene
Volume28
Issue number1
DOIs
Publication statusPublished - 08 Jan 2009

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

Fingerprint Dive into the research topics of 'Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells.'. Together they form a unique fingerprint.

  • Cite this