Induction of p53-dependent, insulin-like growth factor-binding protein-3-mediated apoptosis in glioblastoma multiforme cells by a protein kinase Calpha antisense oligonucleotide.
Induction of p53-dependent, insulin-like growth factor-binding protein-3-mediated apoptosis in glioblastoma multiforme cells by a protein kinase Calpha antisense oligonucleotide.
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DOI：
10.1124/mol.55.2.396
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发表时间：
1999-02
影响因子：
3.6
通讯作者：
L. Shen;N. Dean;R. Glazer
中科院分区：
文献类型：
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作者：
L. Shen;N. Dean;R. Glazer
蛋白激酶Calpha（PKCalpha）表达与多形性胶质母细胞瘤（GBM）（成人中最常见的恶性脑肿瘤）的肿瘤进展相关。为了确定PKCa是否调节GBM中的抗凋亡存活途径，用PKCa选择性反义寡核苷酸处理A172 GBM细胞。PKCalpha反义寡核苷酸处理伴随着PKCalpha水平的降低和处理后24-72小时野生型p53和胰岛素样生长因子结合蛋白-3（IGFBP 3）的诱导，这段时间与通过DNA片段化检测到的凋亡性细胞死亡的出现相一致。Bcl-XL、Bax和p21（WAF 1）水平无显著变化。PKCalpha下调后p53的诱导与mRNA表达的增加无关，但IGFBP 3水平的增加伴随着mRNA水平的增加。重组人IGFBP 3诱导的凋亡作用与PKCalpha反义寡核苷酸相似，其作用可被IGF-I阻断。这些结果表明，PKCalpha在GBM细胞中产生其抗凋亡活性的一种机制是通过抑制p53介导的IGFBP 3活化。
Protein kinase Calpha (PKCalpha) expression is related to tumor progression in glioblastoma multiforme (GBM), the most common malignant brain tumor in adults. To determine whether PKCalpha regulates an anti-apoptotic survival pathway in GBM, A172 GBM cells were treated with a PKCalpha-selective antisense oligonucleotide. PKCalpha antisense oligonucleotide treatment was accompanied by reduction in PKCalpha 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 p21(WAF1). Induction of p53 after PKCalpha 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 PKCalpha antisense oligonucleotide, and its effect was blocked by IGF-I. These results suggest that one mechanism by which PKCalpha produces its antiapoptotic activity in GBM cells is by suppressing the p53-mediated activation of IGFBP3.