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Tumor Biology |
expression in human glioma cells by a proteasome-independent pathway: Implications for in vivo therapy
Department of Pathology (E.W.N., M.A.A., T.S., L.L., Y.L., M.F., D.C.M., D.Z.); Division of Neuropathology and Department of Neurosurgery (D.C.M., D.Z.); New York University Cancer Institute (E.W.N., D.C.M., D.Z.), New York University School of Medicine, New York, NY 10016, USA
2 Address correspondence to Elizabeth W. Newcomb, Department of Pathology, New York University School of Medicine, 550 First Avenue, MSB531, New York, NY 10016 (newcoe01{at}med.nyu.edu).
Abstract
Angiogenesis is a critical step required for sustained tumor growth and
tumor progression. The stimulation of endothelial cells by cytokines secreted
by tumor cells such as vascular endothelial growth factor (VEGF) induces their
proliferation and migration. This is a prominent feature of high-grade
gliomas. The secretion of VEGF is greatly upregulated under conditions of
hypoxia because of the transcription factor hypoxiainducible factor
(HIF)-1
, which controls the expression of many genes, allowing rapid
adaptation of cells to their hypoxic microenvironment. Flavopiridol, a novel
cyclin-dependent kinase inhibitor, has been attributed with antiangiogenic
properties in some cancer cell lines by its ability to inhibit VEGF
production. Here, we show that flavopiridol treatment of human U87MG and T98G
glioma cell lines decreases hypoxia-mediated HIF-1 expression, VEGF
secretion, and tumor cell migration. These in vitro results correlate with
reduced vascularity of intracranial syngeneic GL261 gliomas from animals
treated with flavopiridol. In addition, we show that flavopiridol
downregulates HIF-1 expression in the presence of a proteasome
inhibitor, an agent that normally results in the accumulation and
overexpression of HIF-1. The potential to downregulate HIF-1
expression with flavopiridol treatment in combination with a proteasome
inhibitor makes this an extremely attractive anticancer treatment strategy for
tumors with high angiogenic activity, such as gliomas.
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