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

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

• Kang YJ
• Kim IY
• Kim EH
• Yoon MJ
• Kim SU
• Kwon TK
• Choi KS

• KMID: 991620
• DOI: http://doi.org/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.

Keyword

apoptosis; astrocytes; glioma; paxilline; TNF-related apoptosis-inducing ligand

MeSH Terms

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