2004 Fiscal Year Final Research Report Summary
APOPTOSIS BY THE INHIBITION OF TELOMERASE ACTIVITY IN CANCER CELLS
| Project/Area Number |
14570457
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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 | Gifu University |
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Principal Investigator |
UEMATSU Takahiro GIFU UNIVERSITY, SCHOOL OF MEDICINE, RESEARCH ASSOCIATE, 大学院・医学研究科, 助手 (90334937)
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| Co-Investigator(Kenkyū-buntansha) |
MORIWAKI Hisataka GIFU UNIVERSITY, SCHOOL OF MEDICINE, PROFESSOR, 大学院・医学研究科, 教授 (50174470)
SHIDOJI Yoshihiro SIEBOLD UNIVERSITY, CELLULAR BIOCHEMISTRY SECTION, PROFESSOR, 看護栄養学部, 教授 (00111518)
SHIRATORI Yoshimune GIFU UNIVERSITY, SCHOOL OF MEDICINE, ASSOCIATE PROFESSOR, 大学院・医学研究科, 助教授 (20313877)
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| Project Period (FY) |
2002 – 2004
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| Keywords | RETINOID / HEPATOCELLULAR CARCINOMA / CANCER CHEMOPREVEN / TELOMERASE / APOPTOSIS / CLONAL DELETION / MOLECULAR MARKETTING / NUCLEAR RECEPTOR |
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| Research Abstract |
We have conducted investigations of chemoprevention of hepatocellular carcinoma (HCC) by retionoids and confirmed the clinical effects of acyclic retionid on second primary hepatocarcinogenesis. Acyclic retinoid prevents hepatocarcinogenesis by eradicating premalignant and latent malignant clones of transformed cells from the liver. We demonstrate the mechanism of this clonal deletion at the cellular level. Production of albumin was recovered while that of AFP-L3 was reduced after exposure of the cells to acyclic retinoid for 2 days. In parallel, both TERT mRNA expression and telomerase activity were down-regulated. The cells subsequently died due to apoptosis. Serial increases in mitochondrial membrane permeability and caspase-9 and -3 activities induced apoptosis. Acyclic retinoid first induces differentiation and reduces telomerase activity. Subsequent late apoptosis completes the clonal deletion of the cells.
We revealed that acyclic retinoid not only binds to nuclear receptors, but also affects membrane receptors. Acyclic retinoid enhanced anti-tumor effects of not only IFN-β but also IFN-α, however, natural retinoic acid (all-trans and 9-cis retinoic acid) failed to exert such effect. This combination effect was likely due to enhanced apoptosis induction as characterized by DNA fragmentation and chromatin condensation. Pretreatment of the HCC cells with acyclic retinoid followed by IFN-β, but not the converse, induced such cytotoxic effect. Acyclic retinoid increased the expression of type 1 IFN receptor (IFNR) and inclusion with anti-type 1 IFNR antibody abolished the synergistic growth suppression by the combination.
We evaluate these results as very important to establish cancer chemoprevention with retionids and to develop novel cancer chemopreventive agents.
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Research Products
(10 results)
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[Journal Article] The ring finger protein, RNF8, interacts with retinoid X receptor α and enhances its transcription-stimulating activity.2004
Author(s)
Takano Y, Adachi S, Okuno M, Muto Y, Yoshioka T, Matsushima-Nishiwaki R, Tsurumi H, Ito K, Friedman SL, Moriwaki H, Kojima S, Okano Y
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Journal Title
J Biol Chem 279
Pages: 18926-18934
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Acyclic retinoid, NIK-333, inhibits N-diethylnitrosamine-induced rat hepatocarcinogenesis through suppression of TGF-α expression and cell proliferation.2004
Author(s)
Kagawa M, Sano T, Ishibashi N, Hashimoto M, Okuno M, Moriwaki H, Suzuki R, Kohno H, Tanaka T
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Journal Title
Carcinogenesis 25
Pages: 979-985
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Intrahepatic cholangiocarcinoma arising 10 years after the excision of congenital extrahepatic biliary dilation : A case report.2002
Author(s)
Goto N, Yasuda I, Uematsu T, Kanemura N, Takai S, Ando K, Kato T, Osada S, Takao H, Saji S, Shimokawa K, Moriwaki H
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Journal Title
J Gastroenterol 36
Pages: 856-862
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Acyclic retinoid induces partial differentiation, down-regulates telomerase reverse transcriptase mRNA expression and telomerase activity, and induces apoptosis in human hepatoma-derived cell lines.2002
Author(s)
Yasuda I, Shiratori Y, Adachi S, Obora A, Takemura M, Okuno M, Shidoji Y, Seishima M, Muto Y, Moriwaki H
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Journal Title
J Hepatol 36
Pages: 660-671
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Synergistic induction of apoptosis by acyclic retinoid and interferon-b in human hepatocellular carcinoma cells.2002
Author(s)
Obora A, Shiratori Y, Okuno M, Adachi S, Takano Y, Matsushima-Nishiwaki R, Yasuda I, Yamada Y, Akita K, Sano T, Shimada J, Kojima S, Okano Y, Friedman SL, Moriwaki H
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Journal Title
Hepatology 36
Pages: 1115-1124
Description
「研究成果報告書概要(欧文)」より
