title: Loss of Runx2 sensitises osteosarcoma to chemotherapy-induced apoptosis.
abstract: BACKGROUND
  Osteosarcoma (OS) is the most common bone malignancy in the paediatric population, principally affecting adolescents and young adults. Minimal advancements in patient prognosis have been made over the past two decades because of the poor understanding of disease biology. Runx2, a critical transcription factor in bone development, is frequently amplified and overexpressed in OS. However, the molecular and biological consequences of Runx2 overexpression remain unclear.
  
  
  METHODS
  si/shRNA and overexpression technology to alter Runx2 levels in OS cells. In vitro assessment of doxorubicin (doxo)-induced apoptosis and in vivo chemosensitivity studies. Small-molecule inhibitor of c-Myc transcriptional activity was used to assess its role.
  
  
  RESULTS
  Loss of Runx2 sensitises cells to doxo-induced apoptosis both in vitro and in vivo. Furthermore, in conjunction with chemotherapy, decreasing Runx2 protein levels activates both the intrinsic and extrinsic apoptotic pathways. Transplanted tumour studies demonstrated that loss of endogenous Runx2 protein expression enhances caspase-3 cleavage and tumour necrosis in response to chemotherapy. Finally, upon doxo-treated Runx2 knockdown OS cells there was evidence of enhanced c-Myc expression and transcriptional activity. Inhibition of c-Myc under these conditions resulted in decreased activation of apoptosis, therefore insinuating a role for c-Myc in dox-induced activation of apoptotic pathways.
  
  
  CONCLUSIONS
  Therefore, we have established a novel molecular mechanism by which Runx2 provides a chemoprotective role in OS, indicating that in conjunction to standard chemotherapy, targeting Runx2 may be a new therapeutic strategy for patients with OS.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Roos
authors.affiliation: Integrative Molecular and Biomedical Sciences Program, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Satterfield
authors.affiliation: Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Shuying
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Integrative Molecular and Biomedical Sciences Program, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fuja
authors.affiliation: Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Shuck
authors.affiliation: Department of Pathology, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: M John
authors.initials: MJ
authors.lastname: Hicks
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.|Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Texas Children's Hospital, Houston, TX 77030, USA.|Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Donehower
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.|Integrative Molecular and Biomedical Sciences Program, Baylor College of Medicine, Houston, TX 77030, USA.|Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Yustein
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics*; D053148:Caspase 3 / Q000235:genetics; D045744:Cell Line, Tumor; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics*; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; C493709:RUNX2 protein, human; D004317:Doxorubicin; D053148:Caspase 3