| Co-Investigator(Kenkyū-buntansha) |
HOSHI Nobuo Fukushima Medical University, Sch. of Med., Research Associate, 医学部, 助手 (70274959)
WATANABE Kazuo Fukushima Medical University, Sch. of Med., Associate Prof., 医学部, 助教授 (80167105)
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| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 1999: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1998: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Research Abstract |
We confirmed that FAS is expressed in human cancers with high frequency and its expression is closely associated with fat metabolism, hormone-sensitivity, cell proliferation and with expression of protein and enzymes engaged in fatty acid metabolism.
(1) Expression of fatty acid synthase (FAS) was mainly detected in hormone-sensitive cells (adrenal, breast, prostate, endometium) or cells with high lipid metabolism (sebaceous glands. fat cells, liver type II alveolar cells of lung) in adult, whereas it was found in proliferating cells of human fetus. Cortical neurons and basket cells of the cerebellum also revealed FAS-expression.
(2) Human cancers were positive for FAS at about 74% (838 cases positive among 1131 cases), with high frequency in breast carcinoma (243/243), bladder carcinoma (55/64), esophageal carcinoma (85/88), and hepatocellular carcinoma (38/47), intermediate frequency in gastric carcinoma (270/434) and lung carcinoma (127/200) and low frequency in soft tissue sarcoma (2
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0/64).
(3) High expression of FAS indicated poor prognosis in breast carcinoma and bladder carcinoma, but not in the others.
(4) MCF-7, a breast cancer cell line, showed rapid increase in FAS-mRNA after treatment with estrogen or progesterone. The effect of estrogen was abolished by tamoxifen.
(5) Eight gastric cancer cell lines revealed FAS-expression and it was closely linked to the expressions of proteins and enzymes involved in fatty acid metabolism. These include acyl-CoA binding protein, acyl-CoA dehydrogenases, lysophosphatidic acid acyltransferase-α and -β, and N-myristoil acyltransferase.
(6) Cerulenin, a specific inhibitor of FAS, arrested cell growth of a human gastric cancer cell line TAKIGAWA, which express FAS-mRNA, within 48 hrs after its treatment. Dead cells increased at about 20% in the treated cells compared with non-treated control but apoptotic cells remained unchanged between both groups.
(7) Cerulenin caused down-reguation of expression of proteins and enzymes related to fatty acid metabolism in a gastric cancer cell line TAKIGAWA, especially in acyl-CoA synthase, very long chain acyl-CoA dehydrogenase, long chain acyl-CoA dehydrogenase, lysophosphatidic acid acyltransferase-β and N-myristoil acyltransferase. Less
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