Molecular targeted drug discovery for cancer cell radiosensitization using RNA aptamars

2010 Fiscal Year Final Research Report

• Project/Area Number: 20200039
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research a proposed research project)
• Allocation Type: Single-year Grants
• Research Field: Radiation science; Living organism molecular science
• Research Institution: Tottori University
• Principal Investigator: KURIMASA Akihiro Tottori University, 大学院・医学系研究科, 准教授 (80343276)
• Co-Investigator(Kenkyū-buntansha): NIWA Ohtaura 放射線医学総合研究所, 重粒子医科学センター, 副センター長 (80093293) ; OKAYASU Ryuichi 放射線医学総合研究所, 重粒子医科学センター, グループリーダー (50356135)
• Project Period (FY): 2008 – 2010
• Keywords: 放射線治療生物学 / 分子標的創薬 / DNA修復 / RNA工学

Research Abstract

It is well known that blocking protein kinases related to DNA repair machinery such as DNA-PKcs, ATM, or ATR enhance sensitivity to ionizing radiation (IR). From this point of view, we expect that tumor cell sensitivity against radiotherapy is enhanced by exploiting this mechanism. Protein kinases related to DNA repair machinery are activated by being phosphorylated. Therefore we attempted making the RNA engineering technology, and will develop new radiation sensitization medicine as a molecular target drug for cancer. In this experiment, we are making RNA aptamers against phosphorylated site of DNA-PKcs by SELEX. In this research, we produced RNA aptamers specific to DNA-PKcs phosphorylation site. Furtheremore their specific template sequences were analyzed by next-generation sequencing technology, and some that may recognize DNA-PKcs specifically were focused. U2OS cells are transfected with the RNA molecules, we tested whether can increase sensitivity of radiation. In conclusion, we found some RNA molecules that enhance sensitivity of radiation for U2OS cells.

Research Products

• [Journal Article] NK314 potentiates anti'tumor activity with adult T-cell leukemia-lymphoma cellsby inhibition of dual targets on topoisomerase II{alpha}c and DNA-dependent protein kinase. (2011)
  • Author(s): Hisatomi T, Sueoka-Aragane N, Sato A, Tomimasu R, Ide M, Kurimasa A, Okamoto K, Kimura S, Sueoka E
  • Journal Title: Blood 117(13) Pages: 3575-84
• [Journal Article] Differential role of DNA-PKcs phosphorylations and kinase activity in radiosensitivity and chromosomal instability. (2011)
  • Author(s): Nagasawa H, Little JB, Lin YF, So S, Kurimasa A, Peng Y, Brogan JR, Chen DJ, Bedford JS, Chen BP
  • Journal Title: Radiat Res 175 Pages: 83-9
• [Journal Article] Involvement of N-acetyltransferase human in the cytotoxic activity of 5-fluorouracil. (2009)
  • Author(s): Takubo K, Tsuchiya H, Kurimasa A, Arnesen T, Ryoke K, Shiota G.
  • Journal Title: Anticaneer Drugs 20(8) Pages: 668-75
• [Journal Article] SIRT2 down- regulation confers resistance to microtubule inhibitors by prolonging chronic mitotic arrest. (2009)
  • Author(s): Inoue T, Nakayama Y, Yamada H, Li YC, Yamaguchi S, Osaki M, Kurimasa A, Hiratsuka M, Katoh M, Oshimura M.
  • Journal Title: Cell Cyele 8(8) Pages: 1279-91
• [Journal Article] Effectiveness of combined treatment using X-rays and a phosphoinositide 3-kinase inhibitor, ZSTK474, on proliferation of HeLa cells in vitro and in vivo.
  • Author(s): Anzai K, Sekine-Suzuki E, Ueno M, Okamura M, Yoshimi H, Dan S, Yaguchi SI, Enami J, Yamori T, Okayasu R
  • Journal Title: Caneer Sei. in press
• [Presentation] Live Cell Imaging and kinetics of DNA double-strand breaks (DBSs)foci in cycling U2OS cells. (2011)
  • Author(s): Kurimasa A, Okuda S, Okada A, Tomimatsu N, Iwabuchi K, Chen DJ.
  • Organizer: Genomic Instability and DNA repair in Keystone symposia on Molecular and Cellular Biology
  • Place of Presentation: Keystone, Colorado, USA
  • Year and Date: 20110130-20110204
• [Presentation] DNA resection by Exol dictates critical DNA repair and damage signaling decisions in response to DNA double-strand breaks. (2011)
  • Author(s): Tomimatsu N, Mukherjee B, Deland K, Kurimasa A, Porteus M, Bolderson E, Khanna KK, Burma S.
  • Organizer: Genomic Instability and DNA repair in Keystone symposia on Molecular and Cellular Biology
  • Place of Presentation: Keystone, Colorado, USA
  • Year and Date: 20110130-20110204
• [Presentation] DNA二本鎖切断再結合におけるATMと53BP1の役割 (2010)
  • Author(s): 井原誠、小林純也、栗政明弘、小松賢志、工藤崇
  • Organizer: 日本放射線影響学会、第53回大会
  • Place of Presentation: 京都テルサ、京都
  • Year and Date: 20101020-20101022
• [Presentation] Analysis of novel phosphorylation site of 53BPI induced by DNA double-strand breaks. (2010)
  • Author(s): Kurimasa A, Nagayoshi Y, Okuda S, Okada A, Tomimatsu N, Iwabuchi K, Chen DJ.
  • Organizer: A-T International Workshop 2010
  • Place of Presentation: Redondo Beach, California, USA
  • Year and Date: 20100411-20100414
• [Presentation] Laser and ionizing radiation induced DSB fbci fbrmation : in vivo real time imaging using modified 53BP1-GFP fusion protein. (2010)
  • Author(s): Kurimasa A, Nagayoshi Y, Okuda S, Okada A, Tomimatsu N, Iwabuchi K, Chen DJ.
  • Organizer: Recent Advances in DNA Repair and Related Studies 6th NIRS International Open Laboratory Workshop
  • Place of Presentation: 放射線医学総合研究所、千葉
  • Year and Date: 2010-03-24
• [Presentation] DNA-PKリン酸化部位に対するRNAアプタマーの作製 (2009)
  • Author(s): 奥田沙奈絵、永吉悠里、岡田茜、押村光雄、汐田剛史、栗政明弘
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 20091001-20091003
• [Presentation] DNA2本鎖切断により誘導される53BP1新規リン酸化部位の解析 (2009)
  • Author(s): 永吉悠里、奥田沙奈絵、岡田茜、押村光雄、汐田剛史、栗政明弘
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 20091001-20091003
• [Presentation] がん放射線治療の展開と生物影響の基礎研究 (2009)
  • Author(s): 丹羽太貫
  • Organizer: 茨城大学理学部量子サイエンスフォーラム 公開シンポジウム第2回Quantum Medicine研究会
  • Place of Presentation: 茨城大学理学部(水戸市文京2-1-1)
  • Year and Date: 2009-01-31
• [Remarks] ホームページ等