title: miR-99b-targeted mTOR induction contributes to irradiation resistance in pancreatic cancer.
abstract: BACKGROUND
  Radiation exerts direct antitumor effects and is widely used in clinics, but the efficacy is severely compromised by tumor resistance. Therefore uncovering the mechanism of radioresistance might promote the development of new strategies to overcome radioresistance by manipulating activity of the key molecules.
  
  
  METHODS
  Immunohistochemistry were used to find whether mTOR were over-activated in radioresistant patients' biopsies. Then Western blot, real-time PCR and transfection were used to find whether radiotherapy regulates the expression and activity of mTOR by modulating its targeting microRNA in human pancreatic cancer cell lines PANC-1, Capan-2 and BxPC-3. Finally efficacy of radiation combined with mTOR dual inhibitor AZD8055 was assessed in vitro and in vivo.
  
  
  RESULTS
  Ionizing radiation promoted mTOR expression and activation in pancreatic cancer cells through reducing miR-99b expression, which negatively regulated mTOR. Novel mTOR inhibitor, AZD8055 (10 nM, 100 nM, 500 nM) synergistically promoted radiation (0-10 Gy) induced cell growth inhibition and apoptosis. In human pancreatic cancer xenografts, fractionated radiation combined with AZD8055 treatment further increased the anti-tumor effect, the tumor volume was shrinked to 278 mm3 after combination treatment for 3 weeks compared with single radiation (678 mm3) or AZD8055 (708 mm3) treatment (P < 0.01).
  
  
  CONCLUSIONS
  Our data provide a rationale for overcoming radio-resistance by combined with mTOR inhibitor AZD8055 in pancreatic cancer therapy.
authors.forename: Feng
authors.initials: F
authors.lastname: Wei
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Yanhai
authors.initials: Y
authors.lastname: Guo
authors.forename: An
authors.initials: A
authors.lastname: Xiang
authors.forename: Guangyi
authors.initials: G
authors.lastname: Wang
authors.forename: Xiaochang
authors.initials: X
authors.lastname: Xue
authors.forename: Zifan
authors.initials: Z
authors.lastname: Lu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy*; D010766:Phosphorylation / Q000528:radiation effects; D011836:Radiation Tolerance / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D011839:Radiation, Ionizing; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C561679:MIRN99 microRNA, human; D035683:MicroRNAs; D009025:Morpholines; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases