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J Biol Chem. 2002 Oct 11;277(41):38930-8. Epub 2002 Jul 22.

GADD153-mediated anticancer effects of N-(4-hydroxyphenyl)retinamide on human hepatoma cells.

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  • 1Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute for Molecular Biology and Genetics, Chonbuk National University Medical School and Hospital, Chonju, Chonbuk 561-712, South Korea.


The anticancer effects of N-(4-hydroxyphenyl)retinamide (4HPR), a potential chemopreventive or chemotherapeutic retinamide, are thought to be derived from its ability to induce apoptosis. However, the mechanism of apoptosis induced by 4HPR remains unclear. Thus, this study was designed to identify the gene(s) responsible for induction of apoptosis by 4HPR. Apoptosis was effectively induced by 4HPR in human hepatoma cells. Using the differential display-PCR method, a gene involved in the response to 4HPR was identified, and cells in which the expression of that gene was modulated were analyzed for survival, induction of apoptosis, and cell cycle. GADD153, a gene involved in growth arrest and apoptosis, was preferentially expressed in human hepatoma cells as well as in other cancer cells during 4HPR-induced apoptosis. 4HPR regulates GADD153 expression at the post-transcriptional level in Hep 3B cells and at the transcriptional and post-transcriptional levels in SK-HEP-1 cells, when assayed by in vitro transfection and mRNA stability experiments. To determine the role of the GADD153 protein overexpression that is induced by 4HPR, Hep 3B cells with ectopic overexpression of GADD153 were found to be growth-arrested (at G(1)) and readily underwent apoptosis following treatment with 4HPR or even when they reached confluence. N-Acetyl-l-cysteine or GADD153 antisense significantly protected the cells from 4HPR-induced apoptosis, accompanying by the inhibition of GADD153 overexpression. Parthenolide-mediated overexpression of GADD153 resulted in enhanced 4HPR-induced apoptosis. These results suggest that GADD153 overexpression induced by 4HPR may contribute to the anticancer effects (induction of apoptosis and growth arrest) of 4HPR on cancer cells.

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