2002 Fiscal Year Final Research Report Summary
Anticancer therapy against hepatocellular carcinoma by survivin targeting
| Project/Area Number |
13670531
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Nagasaki University |
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Principal Investigator |
NAKAO Kazuhiko Health Research Center, Associate professor, 保健管理センター, 助教授 (00264218)
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| Co-Investigator(Kenkyū-buntansha) |
ISHII Nobuko Health Research Center, Professor, 保健管理センター, 教授 (20088868)
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| Project Period (FY) |
2001 – 2002
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| Keywords | Survivin / Interferon-α / Hepatoma / TRAIL / siRNA |
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| Research Abstract |
Survivin, which is expressed in cancer tissues including hepatocellular carcinoma but not in normal tissues, represses the activities of caspases resulting in resistance of cancer cells to Fas- or chemotherapeutic agent-mediated apoptosis. In addition, inhibition of survivin expression, by transduction with anti-sense oligonucleotides or a dominant-negative expression vehicle, sensitized cancer cells to chemotherapeutic agent-mediated apoptosis. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, induces apoptosis in a variety of cancer cells with little or no effect on normal cells. Human hepatoma cells, however, are resistant to TRAIL-induced apoptosis. Recently, Griffith et al. reported that the cellular level of survivin is closely relevant to the resistance against TRAIL-mediated apoptosis of renal cell carcinoma cells. In the present study, we have shown that the preincubation with 1,000 IU of IFN-α apparently enhanced the TRAIL-induced apoptosis in HuH-7, Hep3B and PLC/PRF/5 human hepatoma cells. The expression of survivin as well as its m-RNA was repressed by IFN-α in these cells. We also demonstrated that ectopic expression of survivin significantly repressed the TRAIL/IFN-α -induced apoptosis of HuH-7 cells. These findings suggest that downregulation of survivin by IFN-α may account for the enhancement of TRAIL-mediated apoptosis by IFN-α, and that TRAIL in combination with IFN-α may have therapeutic potential in the treatment of human hepatocellular carcinoma.
We also found that down regulation of surviving expression by siRNA transfection sensitized human hepatoma cells to TRAIL-induced apoptosis.
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Research Products
(6 results)
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[Publications] Masaya Shigeno, Kazuhiko Nakao, Tatsuki Ichikawa, Kasumi Suzuki, Atsushi Kawakami, Seigou Abiru, Seiji Miyazoe, Yuichi Nakagawa, Hiroki Ishikawa, Keisuke Hamasaki, Keisuki Nakata, Nobuko Ishii, Katsumi Eguchi: "Interferon-α sensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-κB inactivation"Oncogene. 22(11). 1653-1662 (2003)
Description
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