Abstract |
p53 mutations are rarely detected in clear cell renal cell carcinoma (CCRCC), but, paradoxically, these tumors remain highly resistant to chemotherapy and death receptor-induced death. Here, we show that the accumulation of hypoxia-inducible factor 2alpha (HIF2alpha), a critical oncogenic event in CCRCC following the loss of von Hippel-Lindau ( VHL) tumor suppressor protein, leads to Hdm2-mediated suppression of p53. Primary CCRCC specimens exhibiting strong hypoxic signatures show increased levels of activated nuclear phospho-Hdm2(Ser(166)), which is concomitant with low p53 expression. The abrogation of Hdm2-p53 interaction using the small-molecule Hdm2 inhibitor nutlin-3 or the downregulation of HIF2alpha via HIF2alpha-specific short hairpin RNA or wild-type VHL reconstitution restores p53 function and reverses the resistance of CCRCC cells to Fas-mediated and chemotherapy-induced cell death. These findings unveil a mechanistic link between HIF2alpha and p53 and provide a rationale for combining Hdm2 antagonists with chemotherapy for the treatment of CCRCC.
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Authors | Andrew M Roberts, Ian R Watson, Andrew J Evans, David A Foster, Meredith S Irwin, Michael Ohh |
Journal | Cancer research
(Cancer Res)
Vol. 69
Issue 23
Pg. 9056-64
(Dec 01 2009)
ISSN: 1538-7445 [Electronic] United States |
PMID | 19920202
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies
- Basic Helix-Loop-Helix Transcription Factors
- CH-11 anti-fas antibody, human
- TP53 protein, human
- Tumor Suppressor Protein p53
- fas Receptor
- endothelial PAS domain-containing protein 1
- Doxorubicin
- MDM2 protein, human
- Proto-Oncogene Proteins c-mdm2
- Proto-Oncogene Proteins c-akt
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Topics |
- Antibodies
(pharmacology)
- Apoptosis
(drug effects, physiology)
- Basic Helix-Loop-Helix Transcription Factors
(metabolism)
- Carcinoma, Renal Cell
(drug therapy, metabolism, pathology)
- Cell Line, Tumor
- Doxorubicin
(pharmacology)
- Drug Resistance, Neoplasm
- Humans
- Kidney Neoplasms
(drug therapy, metabolism, pathology)
- Phosphorylation
- Proto-Oncogene Proteins c-akt
(metabolism)
- Proto-Oncogene Proteins c-mdm2
(biosynthesis, metabolism)
- Tumor Suppressor Protein p53
(biosynthesis, metabolism)
- fas Receptor
(physiology)
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