| Project/Area Number |
13470341
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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 |
Urology
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| Research Institution | Keio University |
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Principal Investigator |
MURAI Masaru Keio University, School of Medicine, Professor, 医学部, 教授 (90101956)
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| Co-Investigator(Kenkyū-buntansha) |
OHIGASHI Takashi Keio University, School of Medicine, Assistant professor, 医学部, 講師 (80185371)
NAKASHIMA Jun Keio University, School of Medicine, Assistant professor, 医学部, 講師 (10167546)
MARUMO Ken Keio University, School of Medicine, Associate professor, 医学部, 助教授 (80138130)
HORIGUCHI Yutaka Keio University, School of Medicine, Assistant professor, 医学部, 講師 (60229234)
OYA Mototsugu Keio University, School of Medicine, Assistant professor, 医学部, 講師 (00213885)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥14,300,000 (Direct Cost: ¥14,300,000)
Fiscal Year 2003: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2001: ¥7,100,000 (Direct Cost: ¥7,100,000)
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| Keywords | bcl-2 / NFkappaB / urological malignancies / STAT3 / molecular targeting / 前立腺癌 / NFκB / アポトーシス / 腎細胞癌 / TRAIL / NF-κB |
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| Research Abstract |
NF-kappa B activity was increased in 15 out of 45 renal cell carcinoma and correlated with serum CRP elevation. Forced expression of antisense cDNA of IkappaBalpha, in TRAIL-sensitive cell lines with a low NF-kappaB activity resulted in constitutive activation of NF-kappaB and resistance to TRAIL-induced apoptosis. Adenoviral expression of a stable form of IkappaBalpha in the TRAIL-resistant cell lines induced apoptosis. An NF-kappaB function inhibitor, DHMEQ, has recently been designed and synthesized. NF-kappaB activation was shown to maintain the viability of bladder cancer cells (KU-19-19) and DHMEQ inhibited constitutively activated NF-kappaB and consequently apoptosis was induced. DHMEQ also induced apoptosis through the inhibition of NFkappaB activity in hormone refractory prostate cancer. Antisense bcl-2 oligodeoxynucleotides significantly decreased the viability of an androgen-independent subline (SCAT cells) derived from mouse androgen-dependent mammary carcinoma cells. Direct sequence analysis showed no mutations in the AR of either androgen-dependent or -independent cells. Antisense bcl-2 oligodeoxynucleotides significantly enhanced DES induced cytotoxicity in hormone independent prostate cancer cells (PC3). Our data suggest that a molecular approach targeting bcl-2 appears to be a promising therapy in hormone independent prostate cancer. Locally advanced RCC cases had a significantly higher rate of increased C/EBP-beta activity determined by EMSA, suggesting that the increased activation of C/EBP-beta may contribute to promote tumor invasiveness and render a malignant phenotype of RCC. Our study also identified STAT3 to be a major mediator of IL-6-induced proliferation of renal cancer cells. Because the Jak specific inhibitor AG 490 effectively inhibited the IL-6-induced STAT3 activity and induced apoptosis, the blockade of the STAT3 signaling pathways is considered to be potentially useful as a novel therapeutic approach for RCC.
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