Down-regulation of Bcl-2 and Bcl-xL expression with bispecific antisense treatment in glioblastoma cell lines induce cell death.
The functions of the antiapoptotic proteins Bcl-2 and Bcl-xL were examined in glioblastoma cells. Expression of both Bcl-2 and Bcl-xL were found to be elevated in protein lysates from seven early passage cell lines derived from human glioblastoma tumors compared with non-neoplastic glial cells. Down-regulation of both bcl-2 and bcl-xL expression in glioblastoma cell lines U87 and NS008 with bcl-2/bcl-xL bispecific antisense oligonucleotide resulted in spontaneous cell death. The mechanism of cell death was partially caspase-dependent. Executioner caspase 6 and caspase 7, but not caspase 3, were involved in apoptosis induced by bcl-2/bcl-xL antisense treatment. Interestingly, western blots failed to demonstrate expression of caspase 3 in two of the seven glioblastoma cell lines examined. The data support the hypothesis that Bcl-2 and Bcl-xL are important in preventing cell death in glioblastoma cells. It also suggests that there are functional pathways capable of successful completion of caspase-dependent cell death in gliomas. These findings support a potential role of bcl-2/bcl-xL bispecifc antisense oligonucleotide therapy as a treatment strategy to enhance caspase-dependent cell death in patients with glioblastoma.
Jiang
Zhihong
Z
Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
Zheng
Xiao
X
Rich
Keith M
KM
D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D005904:Glial Fibrillary Acidic Protein; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D020169:Caspases