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Hypoxia and retinoic acid-inducible NDRG1 expression is responsible for doxorubicin and retinoic acid resistance in hepatocellular carcinoma cells

Cited 28 time in Web of Science Cited 33 time in Scopus
Authors
Jung, Eun Uk; Yoon, Jung-Hwan; Lee, Youn-Jae; Lee, Jeong-Hoon; Yu, Su Jong; Kim, Yoon Jun; Lee, Hyo-Suk; Myung, Sun Jung; Kim, Bo Hyun
Issue Date
2010-12-01
Publisher
ELSEVIER IRELAND LTD
Citation
CANCER LETTERS; Vol.298 1; 9-15
Keywords
Hepatocellular carcinomaHypoxiaRetinoic acidDoxorubicinN-myc downstream-regulated gene-1
Abstract
Hypoxia may activate survival signals in cancer cells. Moreover, hypoxic cells are less sensitive than normoxic cells to doxorubicin cytotoxicity, a potent activator of the p53 tumor suppressor gene. N-myc downstream-regulated gene-1 (NDRG1) is a hypoxia- and retinoic acid-inducible protein, and has been previously implicated in carcinogenesis. As this protein is also a downstream target of p53 and hepatocellular carcinoma (HCC) cells frequently evidence resistance to retinoic acid (RA) cytotoxicity, we attempted to determine whether the suppression of NDRG1 expression may sensitize HCC cells to doxorubicin and/or RA cytotoxicity. HCC cells expressed NDRG1 protein, and the expression of this protein was hypoxia- and RA-inducible. Doxorubicin treatment induced HCC cell cytotoxicity via the activation of mitochondrial apoptotic signals, including caspase-9 activation. Hypoxic HCC cells are less sensitive to doxorubicin-induced apoptosis. The suppression of NDRG1 expression either by siRNA or flavopiridol sensitized hypoxic HCC cells to doxorubicin cytotoxicity, and this was attributed to more profound augmentation of JNK and caspase-9 activation. The suppression of NDRG1 expression also sensitized RA-resistant HCC cells to RA-induced apoptosis, and this sensitization was more apparent in hypoxic HCC cells than in normoxic cells. Glutaredoxin2 expression was down-regulated in NDRG1-suppressed HCC cells. These results show that hypoxia- and RA-inducible NDRG1 expression is responsible for doxorubicin and RA resistance in HCC cells. Thus, the selective interruption of NDRG1 signaling may prove to be therapeutically useful in HCCs, particularly in the advanced infiltrative type of tumors exposed to hypoxic environments. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
ISSN
0304-3835
Language
English
URI
https://hdl.handle.net/10371/77627
DOI
https://doi.org/10.1016/j.canlet.2010.05.020
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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