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Advances in Brief |
Nelson Institute of Environmental Medicine, and Kaplan Comprehensive Cancer Center, New, York University School of Medicine, New York, New York 10016 [K. S., M. C.], and Medicine Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892 [W. D. F. and M. V. B.]
Hypoxia limits tumor growth but selects for higher metastatic potential.
We tested the functional activity of hypoxia-inducible factor-1 (HIF-1)
in prostate cell lines ranging from normal epithelial cells (PrEC),
hormone-dependent LNCaP, hormone-independent DU145, PC-3 to
highly metastatic PC-3M cancer cell lines. We found that
HIF-1-stimulated transcription was the lowest in PrEC and LNCaP cells
and the highest in PC-3M cells. The induction by hypoxia of the HIF-1
dependent genes Cap43 and GAPDH
was the highest in the most aggressive PC-3M cancer cells. Because
these advanced prostate cancer cell lines have lost p53 function, this
further shifts a balance from p53 to HIF-1 transcriptional regulation,
and a high ratio of HIF-1-dependent:p53-dependent transcription
was a marker of the advanced malignant phenotype. Transient
transfection of HIF-1
expression vector induced transcription from
p21 promoter construct in prostate cancer cell lines. Furthermore,
hypoxia slightly induced p21 mRNA in these cells. However, neither
expression of p21 nor hypoxia caused growth arrest in PC-3M cells.
Therefore, high inducibility of HIF-1-dependent genes, loss of p53
functions with high ratio of HIF-1-dependent:p53-dependent
transcription, and loss of sensitivity to p21 inhibition is a part of
hypoxic phenotype associated with aggressive cancer behavior.
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