| Project/Area Number |
16591629
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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 |
Urology
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| Research Institution | University of Occupational and Environmental Health, Japan |
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Principal Investigator |
FUJIMOTO Naohiro University of Occupational and Environmental Health, School of Medicine, Associate Professor, 医学部, 助教授 (30209100)
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| Co-Investigator(Kenkyū-buntansha) |
NOMURA Masayoshi University of Occupational and Environmental Health, School of Medicine, Assistant, 医学部, 助手 (80369066)
佐藤 英樹 産業医科大学, 医学部, 助手 (00309973)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2005: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2004: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | prostate cancer / androgen sensitivity / androgen receptor |
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| Research Abstract |
Although androgen-hypersensitivity is one of the possible pathways of hormone-resistance in prostate cancer, the mechanisms of androgen-hypersensitivity are still largely unknown. Using androgen-hypersensitve prostate cancer cells LN-TR2, established from androgen-sensitive LNCaP cells by the long term treatment with tumor necrosis factor α, serum level of which increases in patients with hormone-refractory prostate cancer, we explored the mechanisms of androgen-hypersensitivity in prostate cancer cells which may thus play a role in hormone-resistance. We examined the androgen receptor (AR) DNA sequence and the expression levels of AR and 8 AR cofactors in LNCaP and LN-TR2 cells. As a result, no novel mutation was developed in AR DNA in LN-TR2 cells. We observed higher expressions of nuclear AR upon androgen-treatment and 2 AR coactivators, ARA55 and TIF2, in LN-TR2 compared to LNCaP cells. An overexpression of ARA55 or TIF2 enhanced androgen-induced AR transcriptional activity in LNCaP cell. In the presence of those AR coactivators, AR activity was observed even at low concentrations of androgen. In 2 of 6 patients, the expression level of ARA55 was higher in cancer cells in hormone-resistant tumor than those in hormone-sensitive tumor. Taken together, our results suggest that prostate cancer cells change androgen-sensitivity by an overexpression of nuclear AR and AR coactivators, thus resulting in transition from androgen-dependent to androgen-independent prostate cancer cells. An increase in nuclear AR and AR coactivators may cause androgen-hypersensitivity of prostate cancer cells and thus play a role in hormone-resistance, at least in some patients with prostate cancer.
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