Induction of p53-dependent, insulin-like growth factor-binding protein-3-mediated apoptosis in glioblastoma multiforme cells by a protein kinase Cα antisense oligonucleotide

Protein kinase C alpha (PKC alpha) expression is related to tumor progression in glioblastoma multiforme (GBM), the most common malignant brain tumor in adults. To determine whether PKC alpha regulates an anti-apoptotic survival pathway in GEM, A172 GEM cells were treated with a PKC alpha-selective antisense oligonucleotide. PKC alpha antisense oligonucleotide treatment was accompanied by reduction in PKC alpha 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-X-L, Bax, and p21(WAF1). Induction of p53 after PKC alpha 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 PKC alpha antisense oligonucleotide, and its effect was blocked by IGF-I. These results suggest that one mechanism by which PKC alpha produces its antiapoptotic activity in GBM cells is by suppressing the p53-mediated activation of IGFBP3.