title: RNA interference-mediated c-MYC inhibition prevents cell growth and decreases sensitivity to radio- and chemotherapy in childhood medulloblastoma cells.
abstract: BACKGROUND
  With current treatment strategies, nearly half of all medulloblastoma (MB) patients die from progressive tumors. Accordingly, the identification of novel therapeutic strategies remains a major goal. Deregulation of c-MYC is evident in numerous human cancers. In MB, over-expression of c-MYC has been shown to cause anaplasia and correlate with unfavorable prognosis.
  
  
  METHODS
  To study the role of c-MYC in MB biology, we down-regulated c-MYC expression by using small interfering RNA (siRNA) and investigated changes in cellular proliferation, cell cycle analysis, apoptosis, telomere maintenance, and response to ionizing radiation (IR) and chemotherapeutics in a representative panel of human MB cell lines expressing different levels of c-MYC (DAOY wild-type, DAOY transfected with the empty vector, DAOY transfected with c-MYC, D341, and D425).
  
  
  RESULTS
  siRNA-mediated c-MYC down-regulation resulted in an inhibition of cellular proliferation and clonogenic growth, inhibition of G1-S phase cell cycle progression, and a decrease in human telomerase reverse transcriptase (hTERT) expression and telomerase activity. On the other hand, down-regulation of c-MYC reduced apoptosis and decreased the sensitivity of human MB cells to IR, cisplatin, and etoposide. This effect was more pronounced in DAOY cells expressing high levels of c-MYC when compared with DAOY wild-type or DAOY cells transfected with the empty vector.
  
  
  CONCLUSIONS
  In human MB cells, in addition to its roles in growth and proliferation, c-MYC is also a potent inducer of apoptosis. Therefore, targeting c-MYC might be of therapeutic benefit when used sequentially with chemo- and radiotherapy rather than concomitantly.
authors.affiliation: Neuro-Oncology Program, University Children's Hospital, Zurich, Switzerland. Andre.vonBueren@kispi.uzh.ch
authors.forename: André O
authors.initials: AO
authors.lastname: von Bueren
authors.forename: Tarek
authors.initials: T
authors.lastname: Shalaby
authors.forename: Christoph
authors.initials: C
authors.lastname: Oehler-Jänne
authors.forename: Lucia
authors.initials: L
authors.lastname: Arnold
authors.forename: Duncan
authors.initials: D
authors.lastname: Stearns
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Alexandre
authors.initials: A
authors.lastname: Arcaro
authors.forename: Martin
authors.initials: M
authors.lastname: Pruschy
authors.forename: Michael A
authors.initials: MA
authors.lastname: Grotzer
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D015536:Down-Regulation / Q000187:drug effects / Q000528:radiation effects; D004358:Drug Therapy; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D011839:Radiation, Ionizing; D011878:Radiotherapy; D019098:Telomerase / Q000235:genetics / Q000378:metabolism
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D019098:Telomerase