Induction of apoptosis in glioblastoma cells by inhibition of protein kinase C and its association with the rapid accumulation of p53 and induction of the insulin-like growth factor-1-binding protein-3.
Increased protein kinase C(alpha) (PKC(alpha)) expression in glioblastoma cells is associated with proliferation and resistance to drug-induced apoptosis by an undefined anti-apoptotic pathway. To clarify the role of PKC in apoptosis, we have investigated the effect of the selective PKC inhibitor Ro 31-8220 (3-[1-[3-(amidinothio)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H -pyrrole-2,5-dione methanesulfonate) in two glioblastoma cell lines whose proliferation is dependent on high levels of PKC(alpha). U-87 and A172 cells treated with an IC50 of Ro 31-8220 exhibited nucleosomal DNA fragmentation that coincided with an increase in the number of apoptotic cells. This effect was preceded by the rapid nuclear accumulation of wild-type p53 within 2 hr, and an increased level of the pro-apoptotic protein, insulin-like growth factor-1-binding protein-3, (IGFBP3) but not other p53-regulated proteins such as p21WAF1 or Bax. Accumulation of p53 was also associated with the hypophosphorylated and activated form of the retinoblastoma tumor suppressor protein (RB) at later times after treatment. These results suggest that PKC(alpha) suppresses apoptosis in glioblastoma cells primarily by restricting the accumulation of p53 and the expression of insulin-like growth factor-1-binding protein, as well as by maintaining RB in an inactive hyperphosphorylated state.
Shen
L
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Department of Pharmacology and Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA.
Glazer
R I
RI
D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D002467:Cell Nucleus / Q000378:metabolism; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D018816:Genes, cdc; D005909:Glioblastoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000096:biosynthesis*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007211:Indoles; D018972:Insulin-Like Growth Factor Binding Protein 3; D016159:Tumor Suppressor Protein p53; D011493:Protein Kinase C; C064758:Ro 31-8220