TRAIL induces proliferation of human glioma cells by c-FLIPL-mediated activation of ERK1/2.

Abstract

TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in TRAIL-sensitive human malignant glioma cells. We show for the first time that TRAIL stimulates cell growth in TRAIL-resistant glioma cells. TRAIL-induced cell growth in resistant cells occurred through increased cell cycle progression as determined by flow cytometry and Western blot analysis of retinoblastoma protein phosphorylation. Western blot analysis of TRAIL-treated resistant cells revealed phosphorylation of ERK1/2 proteins and in vitro kinase analysis confirmed the activation of the ERK1/2 kinases. Inhibition of MEK1 eliminated both TRAIL-induced ERK1/2 activation and cell proliferation. In addition, siRNA inhibition of c-FLIP expression eliminates TRAIL-induced ERK1/2 activation and proliferation. Furthermore, overexpression of c-FLIP(L) potentiates TRAIL-induced ERK1/2 activation and proliferation of resistant glioma cells. Our results have shown for the first time that TRAIL-induced ERK1/2 activation and proliferation of TRAIL-resistant human glioma cells is dependent upon the expression of the long form of the caspase-8 inhibitor c-FLIP(L).

• Authors: U Vilimanovich, V Bumbasirevic
• Journal: Cellular and molecular life sciences : CMLS (Cell Mol Life Sci) Vol. 65 Issue 5 Pg. 814-26 (Mar 2008) ISSN: 1420-682X [Print] Switzerland
• PMID: 18239851 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CASP8 and FADD-Like Apoptosis Regulating Protein
• CFLAR protein, human
• RNA, Small Interfering
• Retinoblastoma Protein
• TNF-Related Apoptosis-Inducing Ligand
• Tumor Necrosis Factor-alpha
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Apoptosis (physiology)
• Blotting, Western
• Brain Neoplasms (metabolism, pathology)
• CASP8 and FADD-Like Apoptosis Regulating Protein (antagonists & inhibitors, genetics, metabolism)
• Cell Cycle (physiology)
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm
• Enzyme Activation
• Flow Cytometry
• Glioma (metabolism, pathology)
• Humans
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Phosphorylation
• RNA, Small Interfering (pharmacology)
• Retinoblastoma Protein (metabolism)
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• Tumor Cells, Cultured
• Tumor Necrosis Factor-alpha (pharmacology)