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Sunitinib deregulates tumor adaptation to hypoxia by inhibiting HIF-1α synthesis in HT-29 colon cancer cells

Cited 19 time in Web of Science Cited 21 time in Scopus
Authors
Shin, Hyun-Woo; Cho, Chung-Hyun; Kim, Tae-You; Park, Jong-Wan
Issue Date
2010-07-23
Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
Citation
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS; Vol.398 2; 205-211
Keywords
SunitinibTumor hypoxiaColony formationProtein synthesisHypoxia-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
URI
http://hdl.handle.net/10371/76478
DOI
https://doi.org/10.1016/j.bbrc.2010.06.060
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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