APRIL, a new member of the tumor necrosis factor family, modulates death ligand-induced apoptosis.
APRIL (a proliferation-inducing ligand) is a newly identified member of the tumor necrosis factor (TNF) family. Tumor growth-promoting as well as apoptosis-inducing effects of APRIL have been described. Here, we report that five of 12 human malignant glioma cell lines express APRIL. APRIL gene transfer experiments revealed that malignant glioma cells are refractory to growth-promoting activity of APRIL in vitro and in vivo. Interestingly, ectopic expression of APRIL confers minor protection from apoptotic cell death induced by the death ligands, CD95 ligand (CD95L) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2 ligand (Apo2L). This antiapoptotic activity is specific for death ligand/receptor-mediated apoptosis since APRIL does not protect glioma cells from the cytotoxicity of the drugs, teniposide, vincristine, lomustine or cisplatin. Ectopic expression of APRIL is associated with the upregulation of X-linked inhibitor of apoptosis protein (XIAP), providing a possible explanation for the antiapoptotic activity observed here. In contrast, APRIL does not regulate the expression levels of the antiapoptotic proteins FLICE-inhibitory protein (FLIP), Bcl-2 or Bcl-X(L). These findings suggest that APRIL is involved in the regulation of death ligand-induced apoptotic signaling in malignant glioma cells.
Roth
W
W
Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Tübingen, Tübingen, Germany.
Wagenknecht
B
B
Klumpp
A
A
Naumann
U
U
Hahne
M
M
Tschopp
J
J
Weller
M
M
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002455:Cell Division; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D014176:Protein Biosynthesis; D011506:Proteins; D012334:RNA, Neoplasm / Q000096:biosynthesis; D053221:TNF-Related Apoptosis-Inducing Ligand; D014162:Transfection; D014407:Tumor Cells, Cultured; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology*; D015854:Up-Regulation; D051636:X-Linked Inhibitor of Apoptosis Protein; D019014:fas Receptor / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011506:Proteins; D012334:RNA, Neoplasm; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C114631:TNFSF13 protein, human; C505654:Tnfsf10 protein, mouse; C491959:Tnfsf13 protein, mouse; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D019014:fas Receptor