Lovastatin induces apoptosis in a primitive neuroectodermal tumor cell line in association with RB down-regulation and loss of the G1 checkpoint.
To develop a new approach to the treatment of primitive neuroectodermal tumors we evaluated the effect of the HMG-CoA reductase inhibitor lovastatin on the Ewing's sarcoma cell line CHP-100. Lovastatin induced neural morphology and markers including neuron-specific enolase and neurofilament protein. The acquisition of neural morphology required new mRNA synthesis, and cDNA microarray analysis confirmed that lovastatin altered the program of gene expression. After morphologic differentiation the cells underwent rapidly progressive apoptosis. In normal development of neuronal progenitors, differentiation signals trigger p21WAF1 accumulation, RB hypophosphorylation, enhanced RB-E2F-1 association, and G1 arrest, and these events have been shown to protect from apoptosis. In contrast, in the Ewing's sarcoma cells lovastatin triggered differentiation without causing cell cycle arrest: p21WAF1 was not induced, RB remained hyperphosphorylated, and RB protein expression and RB-E2F-1 association were markedly downregulated, suggesting that loss of an RB-regulated G1 checkpoint promoted apoptosis. Consistent with this hypothesis, adenoviral p21WAF1 decreased DNA synthesis and partially protected from lovastatin-induced cytotoxicity. The data demonstrate a new model for examining the genetic regulation of cell fate in a neural progenitor tumor and suggest a new approach to the treatment of this neoplasm.
Kim
J S
JS
Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, MD 20892, USA.
Pirnia
F
F
Choi
Y H
YH
Nguyen
P M
PM
Knepper
B
B
Tsokos
M
M
Schulte
T W
TW
Birrer
M J
MJ
Blagosklonny
M V
MV
Schaefer
O
O
Mushinski
J F
JF
Trepel
J B
JB
D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000032:analysis; D018797:Cell Cycle Proteins; D048429:Cell Size / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects; D004475:Ectoderm / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects*; D018816:Genes, cdc; D006801:Humans; D007150:Immunohistochemistry; D008148:Lovastatin / Q000494:pharmacology*; D008855:Microscopy, Electron, Scanning; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008940:Mitotic Index; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D016160:Retinoblastoma Protein / Q000378:metabolism*; D012512:Sarcoma, Ewing / Q000473:pathology / Q000648:ultrastructure; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D015415:Biomarkers; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008869:Microtubule-Associated Proteins; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA; D008148:Lovastatin