Development of new therapy for pancreas cancer using PPAR γ-ligand targeting hTERT.
| Project/Area Number |
16590611
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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 | Sapporo Medical University |
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Principal Investigator |
WATANABE Naoki Sapporo Medical University, School of Medicine, Professor, 医学部, 教授 (10158644)
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| Co-Investigator(Kenkyū-buntansha) |
TSUJI Naoki Sapporo Medical University, School of Medicine, Assistant, 医学部, 助手 (00347171)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Keywords | PPAR γ-ligand / 15-Deoxy-Δ^<12,14>-prostaglandin J_2 / Human telomerase reverse transcriptase / Pancreas cancer / PPARγ-ligand / human telomerase reverse transcriptase / Pancreas Cancer / Prostaglandin J2 |
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| Research Abstract |
To investigate the cytotoxic effect of PPAR γ-ligand in pancreas cancer cells, we cultured MIAPaCa-2 cells with various concentrations of 15-deoxy-Δ^<12,14>-prostaglandin J_2 (15d-PGJ_2) for 72 h and determined viable cells number. 15d-PGJ_2 decreased the viable cell number in a dose-dependent manner. Specifically, the proportion of viable cells in 20 μM of 15d-PGJ_2-treated cells decreased to 20% of untreated cells.
We then determined the expression level of hTERT mRNA and protein in 15d-PGJ_2-treated MIAPaCa-2 cells. 15d-PGJ_2 strongly inhibited both hTERT mRNA and protein expression.
Since it has been reported that transcription factor Sp1, c-Myc and estrogen receptor (ER) promote transcription of hTERT gene, we examined DNA binding activity of these three molecules to the hTERT promoter in 15d-PGJ_2-treated cells using EMSA. Down-regulation of DNA binding activity by 15d-PGJ_2 was observed only in ER. We next investigated the effect of 15d-PGJ_2 on the expression of ER. Although MIAPaCa-2 cells expressed only ERβ, expression level of ERβ was not affected by 15d-PGJ_2.
There is a possibility that phosphorylation of serine residues in ERβ enhances its DNA binding activity as well as ERα. We assessed expression of phosphorylated ERβ in 15d-PGJ_2-treated cells. Phosphorylated ERβ was down-regulated by 15d-PGJ_2.
In addition, we investigated the activity of MAP kinase which is speculated to phosphorylate the serine residues in ERβ. MAP kinase activity was assessed by expression of phosphorylated ERK. 15d-PGJ_2 reduced phosphorylated ERK expression.
These results revealed 15d-PGJ_2 inhibit the growth of pancreas cancer cells by down-regulation of hTERT via inhibiting the phosphorylation of ERβ. This study indicates the possibility that PPAR γ-ligand become a new agent for treatment of pancreas cancer.
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Report
(3 results)
Research Products
(13 results)
