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Sunitinib deregulates tumor adaptation to hypoxia by inhibiting HIF-1α synthesis in HT-29 colon cancer cells
Cited 20 time in
Web of Science
Cited 22 time in Scopus
- Authors
- Issue Date
- 2010-07-23
- Publisher
- ACADEMIC PRESS INC ELSEVIER SCIENCE
- Citation
- BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS; Vol.398 2; 205-211
- Keywords
- Sunitinib ; Tumor hypoxia ; Colony formation ; Protein synthesis ; Hypoxia-inducible factor 1
- Abstract
- Sunitinib (SU11248, Sutent (R)) is a class III/V receptor tyrosine kinase (RTK) inhibitor that exhibits potent anti-angiogenic and anticancer activities. Preclinical studies demonstrated that the sunitinib effects are attributed to inhibition of VEGFR and PDGFR phosphorylation. However, even in colon cancer cells lacking sunitinib-targeted RTKs, sunitinib effectively inhibits tumor growth in a xenograft model, and this raises a question about the mechanism underlying the in vivo anticancer action of sunitinib. Since hypoxia is a critical microenvironment that tumors face, we addressed the possibility that sunitinib deregulates tumor adaptation to hypoxia. First we found that sunitinib limits the colony growth of HT-29, which is a colon adenocarcinoma cell line lacking the RTKs, and that HIF-1 alpha in the colonies is decreased by sunitinib. In cultured HT-29 cells, sunitinib suppressed HIF-1 alpha under hypoxic conditions. Moreover, sunitinib repressed the activity of HIF-1 alpha and subsequently decreased the expressions of HIF-1 downstream genes. Mechanistically, sunitinib blocked the 5`-UTR-dependent translation of HIF-1 alpha. The HIF-1 alpha suppression by sunitinib was also reproduced in a VHL-null renal cell carcinoma cell line, where HIF-1 alpha is not degradable. In conclusion, the sunitinib inhibition of HIF-1 signaling could restrain tumor progression in hypoxic regions, which may contribute to anticancer effect of sunitinib. (C) 2010 Elsevier Inc. All rights reserved.
- ISSN
- 0006-291X
- Language
- English
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