Clarification of action mechanism of caspase-activating molecules and cancer cell-selective induction of apoptosis

• Project/Area Number: 24550189
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Chemistry related to living body
• Research Institution: Nara Institute of Science and Technology
• Principal Investigator: MATSUO Takashi 奈良先端科学技術大学院大学, 物質創成科学研究科, 准教授 (50432521)
• Co-Investigator(Renkei-kenkyūsha): HIROTA Shun 奈良先端科学技術大学院大学, 物質創成科学研究科, 教授 (90283457)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: カスパーゼ / 有機小分子 / アポトーシス / 作用機構 / PAC-1 / 活性化 / 速度論

Outline of Final Research Achievements

Caspase-3, a protease at the downstream of a apoptosis cascade, is produced from a zymogen protein (procaspase-3) with the help of other activator on cell stimuli. The activation process is inhibited in several kinds of cancerous cell because of much amounts of metal ions. This work focuses on the action mechanism of PAC-1, a compoound that recovers the activation process of procaspase-3 in cencerous cells, on the activities of (pro)caspase-3 from the viewpoint of enzymology. The kinetic studies of caspase-3 indicated that PAC-1 enhances the activity of mature caspase-3 as well as the recovery of activation process from the zymogen to mature form in the absence of metal ions. The effect of the compound on a mutant procaspase-3, a variant that has a weak caspase-3 activity, was found to be poor. In conclusion, PAC-1 has a structural perturbation mechanismis for affecting the (pro)caspase-3 activities as well as the metal ion-chelation removal pathway.

Research Products

• [Journal Article] Relationship between the Electron Density of the Heme Fe Atom and the Vibrational Frequencies of the Fe-Bound Carbon Monoxide in Myoglobin (2013)
  • Author(s): R. Nishimura, T. Shibata, H. Tai, I. Ishigami, T. Ogura, S. Nagao, T. Matsuo, S. Hirota, K. Imai, S. Neya, A. Suzuki, and Y, Yamamoto
  • Journal Title: Inorg. Chem. Volume: 52 Issue: 6 Pages: 3349-3355
  • DOI: 10.1021/ic3028447
  • Peer Reviewed
• [Journal Article] Electronic Control of Discrimination between O2 and CO in Myoglobin Lacking the Distal Histidine Residue (2013)
  • Author(s): R. Nishimura, T. Shibata, I. Ishigami, T. Ogura, H. Tai, S. Nagao, T. Matsuo, S Hirota, O. Shoji, Y. Watanabe, K. Imai, S. Neya, A. Suzuki, Y. Yamamoto
  • Journal Title: Inorg. Chem. Volume: 53 Issue: 2 Pages: 1091-1099
  • DOI: 10.1021/ic402625s
  • Peer Reviewed
• [Journal Article] Relationship between Oxygen Affinity and Autoxidation of Myoglobin (2012)
  • Author(s): T. Shibata, D. Matsumoto, R. Nishimura, H. Tai, A. Matsuoka, S. Nagao, T. Matsuo, S. Hirota, K. Imai, S. Neya, A. Suzuki, and Y. Yamamoto
  • Journal Title: Inorg. Chem. Volume: 51 Issue: 21 Pages: 11955-11960
  • DOI: 10.1021/ic301848t
  • Peer Reviewed
• [Presentation] 成熟型および前駆体Caspase-3に対するPAC-1の効果 (2015)
  • Author(s): 石田昌也、松尾貴史、廣田俊
  • Organizer: 日本化学会第95春季年会
  • Place of Presentation: 日本大学理工学部・薬学部キャンパス（千葉県船橋市）
  • Year and Date: 2015-03-26 – 2015-03-29
• [Presentation] プロトマーインターフェイスへの合成分子の結合に基づくカスパーゼ３活性の制御 (2014)
  • Author(s): 松尾貴史、山田啓太、三浦仁志、廣田俊
  • Organizer: 第8回バイオ関連化学シンポジウム
  • Place of Presentation: 岡山大学津島キャンパス（岡山市北区）
  • Year and Date: 2014-09-10 – 2014-09-12
• [Presentation] 有機小分子PAC-1によるカスパーゼ3活性の促進機構の検討 (2014)
  • Author(s): 松尾貴史、山田啓太、河野尊匡、廣田 俊
  • Organizer: 日本化学会第94春季年会
  • Place of Presentation: 名古屋大学（愛知県名古屋市千種区）
• [Presentation] アデニル酸キナーゼの構造変化に基づくピレンモノマー/エキシマースイッチングシステムの構築
  • Author(s): 藤井 亮
  • Organizer: 日本化学会第93春季年会
  • Place of Presentation: 立命館大学びわこ・くさつキャンパス
• [Remarks] 松尾貴史ホームページ
  • URL: http://mswebs.naist.jp/LABs/hirota/tmatsuo/matsuo_jpn.html
• [Remarks] 奈良先端科学技術大学院大学 物質創成科学研究科 超分子集合体科学研究室 松尾貴史ホームページ
  • URL: http://mswebs.naist.jp/LABs/hirota/tmatsuo/matsuo_jpn.html
• [Remarks] 松尾貴史ホームページ
  • URL: http://mswebs.naist.jp/LABs/hirota/tmatsuo/matsuo_jpn.html