Identification of cell surface/secreted proteins that affect antitumor activity upon treatment with a Golgi-disruptor, M-COPA
Project/Area Number |
17K07230
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Tumor therapeutics
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Research Institution | Japanese Foundation for Cancer Research |
Principal Investigator |
Ohashi Yoshimi 公益財団法人がん研究会, がん化学療法センター 分子薬理部, 主任研究助手 (50727427)
|
Project Period (FY) |
2017-04-01 – 2020-03-31
|
Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
|
Keywords | ゴルジ体 / Arf1 / 癌 / 蛋白質 / 発現制御 / 分子標的治療 |
Outline of Final Research Achievements |
M-COPA, a Golgi disruptor that we previously developed, efficiently destroyed tumor spheroids of human gastric cancer cell line MKN1 under the 3-dimensional culture conditions. To clarify the antitumor mode of action of M-COPA in 3D culture condition, we screened cell surface proteins downregulated upon treatment with M-COPA by flow cytometry. As a result, we found one of the integrin family proteins significantly downregulated by M-COPA. Interestingly, functional inhibition of the integrin by the use of neutralizing antibody or siRNA efficiently suppressed sphere formation of MKN-1. Moreover, M-COPA downregulated one of the extracellular matrix proteins that serves as a specific ligand for the integrin identified above. These results indicated that integrin signal could be a potential target for gastric cancer therapy and M-COPA could be a promising candidate to this aim.
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Academic Significance and Societal Importance of the Research Achievements |
ゴルジ体は、翻訳されたタンパク質が糖鎖修飾やプロセッシングを経て機能タンパク質として成熟し、細胞内・細胞外・細胞表面の予定された正しい部位に輸送される過程を調節している。スフェロイド培養は、単層培養と比較し、細胞接着が三次元に形成され、in vivoの腫瘍を模倣していると考えらえる。本研究では、ゴルジ体阻害剤によって特定のインテグリンの細胞表面発現やそのリガンドとなる細胞外マトリクス分子の細胞外への分泌を抑制し、その結果、腫瘍塊が崩壊するということを見出した。本研究の成果により、ゴルジ体阻害、ないし別の方法で当該シグナルを抑制することが、がん治療薬開発の新たな戦略となりうることが示された。
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Report
(4 results)
Research Products
(16 results)
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[Journal Article] Targeting the Golgi apparatus to overcome acquired resistance of non-small cell lung cancer cells to EGFR tyrosine kinase inhibitors2017
Author(s)
Yoshimi Ohashi, Mutsumi Okamura, Ryohei Katayama, Siyang Fang, Saki Tsutsui, Akinobu Akatsuka, Mingde Shan, Hyeong-Wook Choi, Naoya Fujita, Kentaro Yoshimatsu, Isamu Shiina, Takao Yamori, and Shingo Dan
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Journal Title
Oncotarget
Volume: 9
Issue: 2
Pages: 1641-1655
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Family-wide Analysis of the Inhibition of Arf Guanine Nucleotide Exchange Factors with Small Molecules: Evidence of Unique Inhibitory Profiles.2017
Author(s)
Benabdi S, Peurois F, Nawrotek A, Chikireddy J, Caneque T, Yamori T, Shiina I, Ohashi Y, Dan S, Rodriguez R, Cherfils J, Zeghouf M.
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Journal Title
Biochemistry (Mosc)
Volume: 56(38)
Issue: 38
Pages: 5125-5133
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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