Role of Src-family kinase in the progression of malignant tumor cells and its clinical implication

• Project/Area Number: 24501361
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Clinical oncology
• Research Institution: Hyogo Medical University
• Principal Investigator: FUJIMORI Yoshihiro 兵庫医科大学, 医学部, 教授 (20229058)
• Co-Investigator(Kenkyū-buntansha): EGUTI Ryoji 兵庫医科大学, 医学部, 助教 (00461088) ; KUBO Syuji 兵庫医科大学, 医学部, 准教授 (10441320)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: Srcファミリーキナーゼ / 中皮腫 / アポトーシス / Fyn / Lyn / スフェロイド / ダサチニブ

Outline of Final Research Achievements

Malignant mesothelioma is an aggressive tumor arising from mesothelial cells of serous membranes. We examined the role of Src family kinases (SFKs) in mesothelioma cells. We found that PP2, a selective SFK inhibitor, inhibited SFK activity and induced apoptosis mediated by caspase-8 in NCI-H28. Src, Yes, Fyn and Lyn protein, which are members of the SFK, were expressed in mesothelioma cell lines, while NCI-H28 cells were deficient in Fyn protein. PP2 reduced Lyn protein levels and suppressed SFK activity. Lyn siRNA induced apoptosis in Fyn-deficient NCI-H28 cells. Double RNAi knockdown of Fyn and Lyn induced apoptosis in Fyn-expressing NCI-H2052 and ACC-MESO-4 cells. Present study suggests that SFK inhibitors induce caspase-8-dependent apoptosis caused by reduction of Lyn protein in Fyn-deficient mesothelioma cells. This provides a new insight for treatment of mesothelioma by simultaneous inhibition of Fyn and Lyn.

Research Products

• [Journal Article] Deficiency of Fyn protein is prerequisite for apoptosis induced by Src family kinase inhibitors in human mesothelioma cells (2012)
  • Author(s): Eguchi R, Kubo S, Takeda H, Ogawa H, et al.(8人中6番)
  • Journal Title: Carcinogenesis Volume: 33 Issue: 5 Pages: 969-975
  • DOI: 10.1093/carcin/bgs109
  • Peer Reviewed
• [Presentation] Deficiency of Fyn Protein Is Prerequisite for Apoptosis Induced by Src Family Kinase Inhibitors in Human Mesothelioma Cells (2012)
  • Author(s): 江口良二、藤盛好啓、小川啓恭
  • Organizer: 第21回日本Cell Death学会
  • Place of Presentation: 名古屋