Abstract
Protein kinase Cα (PKCα) expression is related to tumor progression in glioblastoma multiforme (GBM), the most common malignant brain tumor in adults. To determine whether PKCα regulates an anti-apoptotic survival pathway in GBM, A172 GBM cells were treated with a PKCα-selective antisense oligonucleotide. PKCα antisense oligonucleotide treatment was accompanied by reduction in PKCα levels and the induction of wild-type p53 and insulin-like growth factor-binding protein-3 (IGFBP3) 24–72 h after treatment, a period that coincided with the appearance of apoptotic cell death as detected by DNA fragmentation. There were no significant changes in the levels of Bcl-XL, Bax, and p21WAF1. Induction of p53 after PKCα down-regulation was not associated with increased mRNA expression, but increased IGFBP3 levels were accompanied by increased mRNA levels. Recombinant human IGFBP3 induced an apoptotic effect that was similar to the PKCα antisense oligonucleotide, and its effect was blocked by IGF-I. These results suggest that one mechanism by which PKCα produces its antiapoptotic activity in GBM cells is by suppressing the p53-mediated activation of IGFBP3.
Footnotes
- Received June 12, 1998.
- Accepted November 3, 1998.
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Send reprint requests to: Dr. Robert Glazer, Department of Pharmacology, Georgetown University Medical Center, 3970 Reservoir Rd. NW, Washington, DC 20007-2195. E-mail: glazerr{at}gunet.georgetown.edu
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This work was supported by National Institutes of Health Grant NS34431 (to R.I.G).
- The American Society for Pharmacology and Experimental Therapeutics
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Induction of p53-Dependent, Insulin-Like Growth Factor-Binding Protein-3-Mediated Apoptosis in Glioblastoma Multiforme Cells by a Protein Kinase Cα Antisense Oligonucleotide
