title: RET activation inhibits doxorubicin-induced apoptosis in SK-N-MC cells.
abstract: BACKGROUND
  Medullary thyroid cancer (MTC) is generally resistant to chemotherapy and the frequent constitutive activation of RET (rearranged during transfection gene) in these tumors might inhibit drug-induced apoptosis.
  
  
  METHODS
  Each RET isoform was separately expressed in SK-N-MC cells (neural crest-derived tumor) and the impact of RET activation on doxorubicin-induced apoptosis was examined.
  
  
  RESULTS
  The activation of RET9 and RET51 in the SK-N-MC cells significantly reduced the doxorubicin-induced apoptosis by 50%, compared to untreated cells. RET activation also induced phosphorylation of ERK (extracellular regulated kinase), but no changes in AKT (serine/threonine kinase) phosphorylation were noted. In the presence of a MAP (mitogen-activated protein) kinase inhibitor or a RET kinase inhibitor, the RET-activated/drug-treated cells displayed nearly 75% and 100% of the doxorubicin-induced apoptosis of the drug-treated cells without RET activation, respectively.
  
  
  CONCLUSIONS
  In SK-N-MC cells, downstream activation of MAP kinase, by both RET9 and RET51, appears to mediate the majority of RET-dependent resistance to chemotherapeutically induced apoptosis. MTC might be rendered more responsive to chemotherapeutic agents by the co-administration of a RET kinase inhibitor.
authors.affiliation: Department of Pediatric Surgery, Children's Medical Center of Dallas, Dallas, TX 75235, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Skinner
authors.forename: Karen E
authors.initials: KE
authors.lastname: Lackey
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Freemerman