TY - JOUR
T1 - Flavopiridol, a protein kinase inhibitor, down-regulates hypoxic induction of vascular endothelial growth factor expression in human monocytes
AU - Melillo, Giovanni
AU - Sausville, Edward A.
AU - Cloud, Kiona
AU - Lahusen, Tyler
AU - Varesio, Luigi
AU - Senderowicz, Adrian M.
PY - 1999/11/1
Y1 - 1999/11/1
N2 - We have investigated the effects of flavopiridol, a novel protein kinase inhibitor that is selective for cyclin-dependent kinases, on hypoxia-induced vascular endothelial growth factor (VEGF) expression in human monocytes. We found that hypoxia induces a time-dependent increase of VEGF mRNA expression and protein levels in human monocytes. Flavopiridol showed a minimal effect on the constitutive levels of VEGF mRNA but completely blocked hypoxia- induced VEGF mRNA and protein expression. The inhibitory effects of flavopiridol on VEGF mRNA induction also occurred in the presence of cycloheximide. The transcriptional activation of either a VEGF promoter- luciferase construct or a hypoxia-inducible factor 1 reporter plasmid was not affected by addition of flavopirldol in transient transfecfion experiments. In contrast, actinomycin D experiments demonstrated that flavopiridol dramatically decreased VEGF mRNA stability. These data provide the first evidence that flavopiridol can affect gene expression by altering mRNA stability. We propose that flavopiridol may interfere with one or more signaling events, leading to hypoxia-induced, protein kinase-modulated, RNA protein binding activity. An important clinical implication of our results is that flavopiridol, presently under investigation in clinical trials, might have antiangiogenic as well as direct antiproliferative effects.
AB - We have investigated the effects of flavopiridol, a novel protein kinase inhibitor that is selective for cyclin-dependent kinases, on hypoxia-induced vascular endothelial growth factor (VEGF) expression in human monocytes. We found that hypoxia induces a time-dependent increase of VEGF mRNA expression and protein levels in human monocytes. Flavopiridol showed a minimal effect on the constitutive levels of VEGF mRNA but completely blocked hypoxia- induced VEGF mRNA and protein expression. The inhibitory effects of flavopiridol on VEGF mRNA induction also occurred in the presence of cycloheximide. The transcriptional activation of either a VEGF promoter- luciferase construct or a hypoxia-inducible factor 1 reporter plasmid was not affected by addition of flavopirldol in transient transfecfion experiments. In contrast, actinomycin D experiments demonstrated that flavopiridol dramatically decreased VEGF mRNA stability. These data provide the first evidence that flavopiridol can affect gene expression by altering mRNA stability. We propose that flavopiridol may interfere with one or more signaling events, leading to hypoxia-induced, protein kinase-modulated, RNA protein binding activity. An important clinical implication of our results is that flavopiridol, presently under investigation in clinical trials, might have antiangiogenic as well as direct antiproliferative effects.
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M3 - Article
C2 - 10554012
AN - SCOPUS:0033231301
VL - 59
SP - 5433
EP - 5437
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 21
ER -