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Identification of the Genes Involved in Enhanced Fenretinide-Induced Apoptosis by Parthenolide in Human Hepatoma Cells

Division of Gastroenterology and Hepatology, The Research Institute of Clinical Medicine, Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Chonju, Chonbuk, Republic of Korea

Requests for reprints: Dae-Ghon Kim, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Keumam-dong 634-18, Dukjin-ku, Chonju, Chonbuk 561-712, Republic of Korea. Phone: 82-63-250-1681; Fax: 82-254-1609; E-mail: daeghon{at}moak.chonbuk.ac.kr.

Fenretinide (N-4-hydroxyphenyl retinamide, 4HPR) is a synthetic anticancer retinoid that is a well-known apoptosis-inducing agent. Recently, we observed that the apoptosis induced by fenretinide could be effectively enhanced in hepatoma cells by a concomitant treatment with parthenolide, which is a known inhibitor of nuclear factor-B (NF-B). Furthermore, treatment with fenretinide triggered the activation of NF-B during apoptosis, which could be substantially inhibited by parthenolide, suggesting that NF-B activation during fenretinide-induced apoptosis has an antiapoptotic effect. This study investigated the molecular mechanism of this apoptotic potentiation by NF-B inhibition. The genes involved in the enhanced fenretinide-induced apoptosis by parthenolide were identified using the differential display-PCR method and subsequent Northern blot or semiquantitative reverse transcriptase PCR analysis. This study identified 35 apoptosis-related genes including 12 unknown genes that were either up- or down-regulated by parthenolide. Interestingly, one up-regulated gene (HA1A2) was isolated and cloned from the liver cDNA, and was found to be identical to ANKRD1, which is also referred to as the CARP gene. Compared with controls treated with an empty vector or with antisense cDNA, the ectopic expression of ANKRD1 led to reduced colony formation and to enhanced apoptotic cell death in hepatoma cells. These results suggest that ANKRD1 and the other genes, whose expressions were substantially modulated by the parthenolide-mediated inhibition of NF-B activation, play roles in the enhanced drug-induced apoptosis. In addition, this study suggests that those identified genes may be useful in anticancer strategies against hepatoma.

Key Words: Fenretinide • apoptosis • parthenolide • ANKRD1/CARP • hepatoma cells

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