2006 Fiscal Year Final Research Report Summary
Chemoprevention of hepatocellular carcinoma by dehydroepiandrosterone and its derivatives
| Project/Area Number |
15390225
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | Tokyo Medical University (2006)
University of Tsukuba (2003-2005) |
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Principal Investigator |
MATSUZAKI Yasushi Tokyo Medical University, Medicine, Professor, 医学部, 教授 (50209532)
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| Co-Investigator(Kenkyū-buntansha) |
SHODA Junichi Tsukuba University, Medicine, Assistant Professor, 大学院・人間総合科学研究科, 講師 (90241827)
UCHIDA Kazuhiko Tsukuba University, Medicine, Associate Professor, 大学院・人間総合科学研究科, 助教授 (90211078)
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| Project Period (FY) |
2003 – 2006
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| Keywords | Dehydroepiandrosterone / Cholesterol / Hepatocellular carcinoma / Oxysterols / Nuclear receptor / GC-MS / LC-MS / MS / Apoptosis |
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| Research Abstract |
Dehydroepiandrosterone (DHEA) is the most abundant adrenal androgenic steroid in young adult humans. The physiological functions of DHEA in preventing human carcinogenesis are still controversial, but a lot of reports have shown that pharmacological doses of DHEA show chemopreventive and anti-proliferative effects on tumors in rodents. The present study was undertaken to obtain basic data and methods for the clinical use of DHEA in the future. The following results were obtained.
1.Sensitive and reliable method for the quantification of DHEA-related steroids by a stable isotope-dilution technique using high-resolution GC-MS was developed. The method made it possible to determine simultaneously DHEA and DHEA derivative levels in human serum. In addition, to evaluate the effects of DHEA on cholesterol metabolism, highly sensitive LC-MS/MS methods for the quantification of several key intermediates in the cholesterol and bile acid biosynthetic pathways were developed.
2.The effects of DHEA
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on the proliferation of hepatic cancer cell lines were studied. We demonstrated the following four mechanisms of the anti-proliferation by DHEA : 1) depletion of NADPH and ribose-5-phosphate due to the inhibition of glucose-6-phosphate dehydrogenase activity, 2) suppression of cholesterol biosynthetic pathway by inhibition of HMG-CoA reductase activity, 3) interference with a cell proliferation signaling pathway (MAPK cascade), and 4)induction of apoptosis through the inhibition of the PI3K/Akt signaling pathway.
3. Hypercholesterolemia is one of the important paraneoplastic syndromes in patients with hepatocellular carcinoma and DHEA inhibits the proliferation of hepatocellular carcinoma by inhibiting cholesterol biosynthetic pathway. Therefore, we investigated the molecular mechanisms of hypercholesterolemia associated with hepatoma by using a hepatoma-bearing rat model. As a result, hypercholesterolemia in the hepatoma-bearing rats was caused by the increased cholesterol efflux from tumors due to the activation of a nuclear receptor, LXRalpha. Over-expression of the sterol regulatory element-binding protein (SREBP) processing system contributes to the activation of LXRalpha by maintaining high tissue levels of oxysterols that are ligands for this nuclear receptor. Less
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