東北大学大学院医学系研究科・医学部

STAFF

Professor

• Hosoi, YoshioProfessor. 細井 義夫 教授
  

Other Faculty / Staff

• Hashimoto, Takuma

  Lect. 橋本 拓磨 講師

• Hatabi, Khaled

  Assistant Prof. Hatabi, Khaled 助教

CONTACT

OUTLINE

1. Elucidation of the mechanisms of radiation resistance induced by hypoxia and/or nutrient starvation
It is known that in cancer tissues, there are tumor cells that are hypoxic due to insufficient angiogenesis compared with the growth rate of the tumor, and that these cells show radiation resistance. Since cells in hypoxia are also generally under nutrient starvation, We are investigating the mechanisms by which hypoxia and/or nutrient starvation induce radiation resistance. We have reported that AMPK, which is a sensor of intracellular energy status, is activated in hypoxia or nutrient starvation, and that ATM and DNA-PKcs, which are DNA double-strand break repair enzymes, are also activated. We are investigating to elucidate the transduction pathways for activation of DNA double-strand breaks repair enzymes such as ATM and DNA-PKcs under hypoxia and/or nutrient starvation.
2. Elucidation of the relationship between stemness and radiation resistance
The concept of stem cells has been established in the fields of normal tissues, but recently stem cells are known to exist in cancer. Stem cells are usually found under hypoxic and nutrient starvation condition, which make the cells radiation resistance. In our laboratory, we are investigating (1) the reason why hypoxia and/or nutrient starvation is necessary for the maintenance of stem cells, and (2) the relationship between stemness and radiation resistance using mesenchymal stem cells, cancer cells, and iPS cells.

1．低酸素・低栄養による放射線抵抗性誘導の機序解明
　癌組織では、腫瘍の増殖速度に比して不十分な血管新生により低酸素状態にある腫瘍細胞が存在し、それらの細胞が放射線抵抗性を示すことが知られています。低酸素状態にある細胞は一般的に低栄養でもあることから、当研究室では低酸素と低栄養が放射線抵抗性を誘導する機序の解明を進めています。これまでに低酸素状態および低栄養状態では共に細胞内のエネルギー状態のセンサーであるAMPKが活性化し、DNA2重鎖切断修復酵素であるATMやDNA-PKcsが活性化する事を明らかにし、現在はそれらの情報伝達経路解明のための研究を続けています。
2．幹細胞の未分化と放射線抵抗性との関係の解明
　幹細胞の概念は正常組織において確立されたものですが、癌にも幹細胞が存在し放射線抵抗性を示すことが報告されています。一般に幹細胞は低酸素・低栄養状態にあることから、放射線抵抗性であることが示唆されます。当研究室では低酸素・低栄養状態が幹細胞の維持に必要な理由と、A 幹細胞であることと放射線抵抗性との関係を解明するための研究を間葉系幹細胞、癌細胞、iPS細胞を用いて進めています。

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  Laboratory
  実験室

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  X-ray irradiation device
  X線照射装置

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  Cell culture room
  細胞培養室

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  Stuff room
  研究室

ARTICLE

Urushihara Y, et al. AMPK/FOXO3a Pathway Increases Activity and/or Expression of ATM, DNA-PKcs, Src, EGFR, PDK1, and SOD2 and Induces Radioresistance under Nutrient Starvation. Int. J. Mol. Sci. 24(16), 12828, 2023.
URL：https://www.mdpi.com/1422-0067/24/16/12828

Hashimoto T, et al. AMPK increases expression of ATM through transcriptional factor Sp1 and induces radioresistance under severe hypoxia in glioblastoma cell lines. Biochemical and Biophysical Research Communications 590:82-88, 2022.
URL：https://www.sciencedirect.com/science/article/pii/S0006291X21017174

Shiga S, et al. DNA-PKcs is activated under nutrient starvation and activates Akt, MST1, FoxO3a, and NDR1. Biochemical and Biophysical Research Communications 521(3):668-673, 2020.
URL：https://www.sciencedirect.com/science/article/pii/S0006291X19320352

Hashimoto T, et al. Severe hypoxia increases expression of ATM and DNA-PKcs and it increases their activities through Src and AMPK signaling pathways. Biochemical and Biophysical Research Communications 505(1):13-19, 2018.
URL：https://www.sciencedirect.com/science/article/pii/S0006291X18319879

Murata Y, et al. Knockdown of AMPKα decreases ATM expression and increases radiosensitivity under hypoxia and nutrient starvation in an SV40-transformed human fibroblast cell line, LM217. Biochemical and Biophysical Research Communications 495(4):2566-2572, 2018．
URL：https://www.sciencedirect.com/science/article/pii/S0006291X1732541X