Radiosensitization of radioresistant cancer stem cells by inhibition of ATM

2013 Fiscal Year Final Research Report

• Project/Area Number: 23659588
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Radiation science
• Research Institution: Tohoku University (2012-2013); Hiroshima University (2011)
• Principal Investigator: HOSOI Yoshio 東北大学, 医学(系)研究科(研究院), 教授 (50238747)
• Project Period (FY): 2011 – 2013
• Keywords: 放射線

Research Abstract

We report herein that ATM can be activated when exposed to hydrogen peroxide without inducing nuclear DDR in Hep G2 cells, and the oxidized cells could be subjected to subcellular fractionation. The first detergent-based fractionation experiment revealed that active, phosphorylated ATM was located in the second fraction, which also contained both mitochondria and peroxisomes. An alternative fractionation method involving homogenization and differential centrifugation, which permits the light membrane fraction containing peroxisomes to be produced, but not mitochondria, revealed that the light membrane fraction contained only traces of ATM. In contrast, the heavy membrane fraction, which mainly contained mitochondrial components, was enriched in ATM and active ATM, suggesting that the oxidative activation of ATM occurs in mitochondria and not in peroxisomes. In Rho 0-Hep G2 cells, which lack mitochondrial DNA and functional mitochondria, ATM failed to respond to hydrogen peroxide.

Research Products

• [Journal Article] Requirement of mitochondria for ATM activation by extranuclear oxidative stress in cultured human hepatoblastoma cell line HepG2 cells (2014)
  • Author(s): Morita A, Murakami T, Morinaga T, Tanimoto K, Hosoi Y
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 443 (Epub) Pages: 1286-90
  • DOI: 10.1016/j.bbrc.2013.12.139
  • Peer Reviewed
• [Journal Article] Evaluation of Zinc (II) chelators for inhibiting p53-mediated apoptosis (2013)
  • Author(s): Morita A, Ariyasu S, Ohya S, Takahashi I, Wang B, Tanaka K, Uchida T, Okazaki H, Hanaya K, Enomoto A, Nenoi M, Ikekita M, Aoki S, Hosoi Y
  • Journal Title: Oncotarget Volume: 4 Pages: 2439-2450
  • URL: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3926839/
  • Peer Reviewed
• [Journal Article] The HSP90 inhibitor 17-allylamino-17-demethoxygeldanamyci n modulates radiosensitivity by downregulating serine/threonine kinase 38 via Sp1 inhibition (2013)
  • Author(s): Enomoto A, Fukasawa T, Takamatsub N, Itob M, Morita A, Hosoi Y, Miyagawa K
  • Journal Title: European Journal of Cancer Volume: 49 (Epub) Pages: 3547-3558
  • DOI: 10.1016/j.ejca.2013.06.034.
  • Peer Reviewed
• [Journal Article] Sodium orthovanadate (vanadate), a potent mitigator of radiation-induced damage to the hematopoietic system in mice (2013)
  • Author(s): Wang B, Tanaka K, Morita A, Ninomiya Y, Maruyama K, Fujita K, Hosoi Y, Nenoi M
  • Journal Title: J. Radiat. Res Volume: 54 Pages: 620-629
  • DOI: 10.1093/jrr/rrs140
  • Peer Reviewed
• [Presentation] 過酸化水素・放射線によるATM を介したp53 Ser-15 のリン酸化とアポトーシス (2011)
  • Author(s): 森田明典、佐藤元俊、谷本圭司、細井義夫
  • Organizer: 日本放射線影響学会第54回大会
  • Place of Presentation: 神戸市
  • Year and Date: 2011-11-19
• [Presentation] 過酸化水素によるATM を介したp53 Ser-15 のリン酸化 (2011)
  • Author(s): 細井義夫、森田明典、谷本圭司
  • Organizer: 第17回国際癌治療増感研究会
  • Place of Presentation: 仙台市
  • Year and Date: 2011-06-24
• [Presentation] 過酸化水素・放射線によるATMを介したp53 Ser15 のリン酸化 (2010)
  • Author(s): 佐藤元俊、川口弦、青山英史、笹井啓資、細井義夫
  • Organizer: 第49回日本医学放射線学会生物部会学術大会
  • Place of Presentation: 札幌市
  • Year and Date: 2010-07-09