| Project/Area Number |
22590704
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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 | Nagoya City University |
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Principal Investigator |
TANIDA Satoshi 名古屋市立大学, 大学院・医学研究科, 助教 (30528782)
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| Co-Investigator(Kenkyū-buntansha) |
JOH Takashi 名古屋市立大学, 大学院・医学研究科, 教授 (30231369)
KATAOKA Hiromi 名古屋市立大学, 大学院・医学研究科, 准教授 (40381785)
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| Co-Investigator(Renkei-kenkyūsha) |
HIGASHIYAMA Shigeki 愛媛大学, 大学院・医学系研究科, 教授 (60202272)
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| Project Period (FY) |
2010 – 2012
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| Project Status |
Completed (Fiscal Year 2012)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2012: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000)
Fiscal Year 2011: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2010: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
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| Keywords | EGFファミリー / HB-EGF核移行シグナル / PLZF / Alphascreen assay / IL-8 / HB-EGF-CTF / colitic cancer / 潰瘍性大腸炎 / 炎症性腸疾患 |
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| Research Abstract |
Current treatment target toward advanced colorectal cancers is mainly focused on the epidermal growth factor receptor (EGFR) signaling, but its additive effects with chemotherapy are still limited. A disintegrin and metalloproteinase (ADAM) cleaves the proheparin-binding epidermal growth factor like growth factor (proHB-EGF). And soluble HB-EGF activates EGFR. In parallel, the carboxy-terminal fragment of proHB-EGF (HB-EGF-CTF) translocate into the inner nuclear membrane, subsequently exerts on the regulation of cell proliferation by binding nuclear promyelocytic leukemia zinc finger (PLZF) protein, a transcriptional repressor, thereby causing its nuclear export. We hypothesized that the inhibition of HB-EGF-CTF nuclear translocation may be a new strategy in preventing cell proliferation.Methods:12-O-tetradecanoylphorbor-13-acetate (TPA) was treated to activate ADAM. Nine-thousand chemical compounds were screened for their efficacies in blocking the binding of HB-EGF-CTF to promyelocyt
… More
ic leukemia zinc finger (PLZF) with Alphascreen system. The obtained candidates were then used to block the binding of HB-EGF-CTF to PLZF in colon cancer cells, HT29 and HCT116. Cell proliferation was investigated with a growth curve assay. The intracellular localization, and association between HB-EGF-CTF and PLZF, was assessed with immunofluorescent staining, and immunoprecipitation and Western blotting, respectively. The effects of obtained candidates on EGFR phosphorylation and on nuclear translocation of HB-EGF-CTF and export of PLZF during the angiotensin II type1 receptor (AT1R) knockdown were also investigated. Results: Telmisartan and candesartan were found to be potential candidates. Telmisartan inhibited TPA-induced cell proliferation stronger than candesartan. Telmisartan, but not candesartan blocked the nuclear translocation of HB-EGF-CTF, and binding of HB-EGF-CTF to PLZF, during TPA stimulation. Both telmisartan and candesartan did not inhibit TPA-induced EGFR phosphorylation, and telmisartan, but not candesartan, inhibited TPA-induced nuclear translocation of HB-EGF-CTF after knockdown of AT1R. Conclusions: The inhibition of HB-EGF-CTF nuclear translocation with telmisartan may be a novel strategy in preventing cell proliferation. Less
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