A novel signaling crosstalk between prostaglandin E2 receptors and IGF-1 receptor as a possible molecular target for antitumor therapy
| Project/Area Number |
15K06873
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Tumor therapeutics
|
|---|
| Research Institution | Musashino University |
|---|
Principal Investigator |
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
上原 久典 徳島大学, 病院, 教授 (30263809)
|
|---|
| Project Period (FY) |
2015-04-01 – 2019-03-31
|
| Project Status |
Completed (Fiscal Year 2018)
|
| Budget Amount *help |
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2015: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
|
|---|
| Keywords | PGE2受容体 / がん / メタボローム / グルタミン酸代謝 / GGCT / シグナルクロストーク |
|---|
| Outline of Final Research Achievements |
Using human pancreatic cancer cells BxPC-3, metabolome analyses were conducted. Compared with IGF-1-treated cells, EP2/EP4 antagonists-pretreated IGF-1-treated cells caused marked increases of metabolites in glutamate-metabolic pathway and coline- metabolic pathway, and apparent decreases of metabolites in pentose-phosphate-metabolic pathway. Of these, gamma-glutamylcyclotransferase (GGCT), which play a role in glutamate-metabolic pathway was further investigated.
Stable knockdown cells derived from BxPC-3 decreased cell growth rate and exhibited G0/G1 arrest. Furthermore, susceptibility to IGF-1-induced growth stimulation was also decreased, whereas effects of EP2/EP4 antagonists on abrogation of IGF-1-induced growth stimulation was diminished. Interestingly, GGCT overexpression in parental BxPC-3 also induced decrease of cell growth rate and ERK activation.
|
| Academic Significance and Societal Importance of the Research Achievements |
本研究によりPGE2受容体とIGF-1受容体のシグナルクロストークには細胞内代謝の変動が関与する事が初めて示された。本研究成果はがん細胞増殖における細胞内シグナル伝達と細胞内代謝変動の相互的な影響を強く示唆するものとして意義深いものである。
GGCTは、腫瘍増殖を促進すると考えられていたが、本検討により過剰な発現もむしろ細胞増殖速度の低下をもたらす事が示された。この結果は生理的発現レベルを逸脱させるとその高低に関わらず深刻な細胞毒性が発揮される事例でと考えられ、この点は、本邦をはじめ世界的に行われている分子標的治療（特に核酸医薬）の判定基準を考慮する際の一材料となる可能性があると考える。
|
Report
(5 results)
Research Products
(12 results)
-
-
-
[Journal Article] Histopathological characteristics of glutamine synthetase-positive hepatic tumor lesion in a mouse model of spontaneous metabolic syndrome (TSOD mouse).2016
Author(s)
Tetsuyuki Takahashi, Takeshi Nishida, Hayato Baba, Hideki Hatta, Johji Imura, Mitsuko Sutoh, Syunji Toyohara, Ryoji Hokao, Syunsuke Watanabe, Hirohisa Ogawa, Hisanori Uehara, Koichi Tsuneyama.
-
Journal Title
Mol. Clin. Oncol.
Volume: 5
Pages: 267-270
Related Report
Peer Reviewed / Int'l Joint Research
-
-
-
-
-
-
-
-
-
