Hyperinducibility of hypoxia-responsive genes without p53/p21-dependent checkpoint in aggressive prostate cancer
Autor: | K, Salnikow, M, Costa, W D, Figg, M V, Blagosklonny |
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Rok vydání: | 2000 |
Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Male Transcriptional Activation Transcription Genetic Cell Cycle Intracellular Signaling Peptides and Proteins Glyceraldehyde-3-Phosphate Dehydrogenases Nuclear Proteins Prostatic Neoplasms Proteins Cell Cycle Proteins Flow Cytometry Hypoxia-Inducible Factor 1 alpha Subunit Cell Hypoxia DNA-Binding Proteins Gene Expression Regulation Neoplastic Cyclins Protein Biosynthesis Tumor Cells Cultured Humans Hypoxia-Inducible Factor 1 Neoplasm Metastasis Tumor Suppressor Protein p53 Promoter Regions Genetic Transcription Factors |
Zdroj: | Cancer research. 60(20) |
ISSN: | 0008-5472 |
Popis: | 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-1alpha 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. |
Databáze: | OpenAIRE |
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