Paxilline enhances TRAIL-mediated apoptosis of glioma cells via modulation of c-FLIP, survivin and DR5

Exp Mol Med. 2011 Jan 31;43(1):24-34. doi: 10.3858/emm.2011.43.1.003.

Abstract

Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) induces apoptosis selectively in cancer cells while sparing normal cells. However, many cancer cells are resistant to TRAIL-induced cell death. Here, we report that paxilline, an indole alkaloid from Penicillium paxilli, can sensitize various glioma cells to TRAIL-mediated apoptosis. While treatment with TRAIL alone caused partial processing of caspase-3 to its p20 intermediate in TRAIL-resistant glioma cell lines, co-treatment with TRAIL and subtoxic doses of paxilline caused complete processing of caspase-3 into its active subunits. Paxilline treatment markedly upregulated DR5, a receptor of TRAIL, through a CHOP/GADD153-mediated process. In addition, paxilline treatment markedly downregulated the protein levels of the short form of the cellular FLICE-inhibitory protein (c-FLIPs) and the caspase inhibitor, survivin, through proteasome-mediated degradation. Taken together, these results show that paxilline effectively sensitizes glioma cells to TRAIL-mediated apoptosis by modulating multiple components of the death receptor-mediated apoptotic pathway. Interestingly, paxilline/TRAIL co-treatment did not induce apoptosis in normal astrocytes, nor did it affect the protein levels of CHOP, DR5 or survivin in these cells. Thus, combined treatment regimens involving paxilline and TRAIL may offer an attractive strategy for safely treating resistant gliomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Astrocytes / metabolism
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Drug Discovery
  • Flow Cytometry
  • Glioma / metabolism*
  • Glioma / pathology
  • Humans
  • Indoles / pharmacology*
  • Inhibitor of Apoptosis Proteins / metabolism
  • RNA, Small Interfering
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Survivin
  • TNF-Related Apoptosis-Inducing Ligand / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*
  • Transcription Factor CHOP / analysis

Substances

  • Antineoplastic Agents
  • BIRC5 protein, human
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Indoles
  • Inhibitor of Apoptosis Proteins
  • RNA, Small Interfering
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Survivin
  • TNF-Related Apoptosis-Inducing Ligand
  • Transcription Factor CHOP
  • paxilline
  • Caspase 3