title: Activation of mTORC1 under nutrient starvation conditions increases cellular radiosensitivity in human liver cancer cell lines, HepG2 and HuH6.
abstract: BACKGROUND
  The presence of unperfused regions containing cells under hypoxic and nutrient starvation conditions contributes to radioresistance in solid human tumors. It is well known that the hypoxia causes cellular radioresistance. However, the effects of nutrient starvation conditions on cellular radiosensitivity remain unclear.
  
  
  METHODS
  Human liver cancer cell lines, HepG2 and HuH6, and a SV40-transformed human fibroblast cell line, LM217 were used to examine the effects of nutrient starvation conditions on cellular radiosensitivity and on activity of mammalian target of rapamycin complex 1 (mTORC1) that senses cellular nutrient conditions and affects radiosensitivity.
  
  
  RESULTS
  In contrast to suppressed mTORC1 activity under nutrient starvation conditions in LM217, HepG2 and HuH6 cells showed increased mTORC1 activity under nutrient starvation conditions. Both AMP-activated protein kinase (AMPK) and Akt were activated under nutrient starvation conditions in all the three cell lines. Under starvation conditions, increased radiosensitivity was observed in HepG2 and HuH6 cells, in contrast to decreased radiosensitivity in LM217 cells. Knockdown of mTOR using siRNA for mTOR or treatment with a mTOR inhibitor, rapamycin, suppressed the increased radiosensitivity under starvation conditions in HepG2 cells.
  
  
  CONCLUSIONS
  Our data show for the first time that nutrient starvation conditions activate mTORC1 and increase radiosensitivity through mTORC1 activation in liver cancer cell lines, HepG2 and HuH6.
authors.affiliation: Department of Radiation Biology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Snedai, Miyagi-ken 980-8575, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Murata
authors.affiliation: Department of Radiation Biology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Snedai, Miyagi-ken 980-8575, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Uehara
authors.affiliation: Department of Radiation Biology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Snedai, Miyagi-ken 980-8575, Japan. Electronic address: hosoi@med.tohoku.ac.jp.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hosoi
mesh_terms: D002470:Cell Survival / Q000528:radiation effects*; D003470:Culture Media / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000503:physiopathology* / Q000532:radiotherapy*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D011836:Radiation Tolerance; D011879:Radiotherapy Dosage; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D003470:Culture Media; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: Liver cancer; Radiosensitivity; Rapamycin; Starvation; mTORC1