title: Extracellular superoxide dismutase induces mouse embryonic fibroblast proliferative burst, growth arrest, immortalization, and consequent in vivo tumorigenesis.
abstract: OBJECTIVE
  Rat sarcoma virus (RAS)-induced tumorigenesis has been suggested to follow a three-stage model consisting of an initial RAS activation, senescence induction, and evasion of p53-dependent senescence checkpoints. While reactive oxygen species act as second messengers in RAS-induced senescence, they are also involved in oncogenic transformation by inducing proliferation and promoting mutations. In the current work, we investigated the role of extracellular superoxide dismutase (SOD3) in RAS-induced senescence and immortalization in vitro and in vivo. We used a mouse embryonic fibroblast (MEF) primary cell model along with immortalized and transformed human cell lines derived from papillary and anaplastic thyroid cancer.
  
  
  RESULTS
  Based on our data, sod3 RNA interference in H-RasV12-transduced cells markedly inhibited cell growth, while sod3 over-expression in MEFs initially caused a proliferative burst followed by the activation of DNA damage checkpoints, induction of p53-p21 signal transduction, and senescence. Subsequently, sod3-transduced MEF cells developed co-operative p21-p16 down-regulation and acquired transformed cell characteristics such as increased telomerase activity, loss of contact inhibition, growth in low-nutrient conditions, and in vivo tumorigenesis. Interestingly, as previously reported with RAS, we showed a dose-dependent response to SOD3 in vitro and in vivo involving transcriptional and non-transcriptional regulatory mechanisms.
  
  
  METHODS
  SOD3 may mediate H-RasV12-induced initiation of primary cell immortalization.
  
  
  CONCLUSIONS
  Our results indicate that SOD3 influences growth signaling in primary and cancer cells downstream of the ras oncogene and could serve as a therapy target at an early tumorigenesis phase.
authors: 1 Department of Molecular Medicine and Medical Biotechnologies, Institute of Experimental Endocrinology and Oncology (CNR), University of Naples Federico II , Naples, Italy .
authors: Maria Domenica
authors: MD
authors: Castellone
authors: Angela
authors: A
authors: Langella
authors: Silvia
authors: S
authors: Cantara
authors: Juha P
authors: JP
authors: Laurila
authors: Lilja E
authors: LE
authors: Laatikainen
authors: Roberto
authors: R
authors: Bellelli
authors: Furio
authors: F
authors: Pacini
authors: Marco
authors: M
authors: Salvatore
authors: Mikko O
authors: MO
authors: Laukkanen
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology; D051379:Mice; D013482:Superoxide Dismutase / Q000378:metabolism*
chemical_list: D013482:Superoxide Dismutase