title: Aberrant lipid metabolism in anaplastic thyroid carcinoma reveals stearoyl CoA desaturase 1 as a novel therapeutic target.
abstract: BACKGROUND
  Currently there are no efficacious therapies for patients with anaplastic thyroid carcinoma (ATC) that result in long-term disease stabilization or regression.
  
  
  OBJECTIVE
  We sought to identify pathways critical for ATC cell progression and viability in an effort to develop new therapeutic strategies. We investigated the effects of targeted inhibition of stearoyl-CoA desaturase 1 (SCD1), a constituent of fatty acid metabolism overexpressed in ATC.
  
  
  METHODS
  A gene array of ATC and normal thyroid tissue was performed to identify gene transcripts demonstrating altered expression in tumor samples. Effects of pharmacological and the genetic inhibition of SCD1 on tumor cell viability as well as cell signaling responses to therapy were evaluated in in vitro and in vivo models of this rare, lethal malignancy.
  
  
  RESULTS
  The gene array analysis revealed consistent distortion of fatty acid metabolism and overexpression of SCD1 in ATC and well-differentiated thyroid carcinomas. SCD1 is critical for ATC cell survival and proliferation, the inhibition of which induced endoplasmic reticulum stress, activation of the unfolded protein response, and apoptosis. Combined suppression of endoplasmic reticulum-associated degradation, a prosurvival component of the unfolded protein response, using proteasome inhibitors resulted in a synergistic decrease in tumor cell proliferation and increased cell death.
  
  
  CONCLUSIONS
  SCD1 is a novel oncogenic factor specifically required for tumor cell viability in ATC. Furthermore, the expression of SCD1 appears to be correlated with thyroid tumor aggressiveness and may serve as a prognostic biomarker. These findings substantiate SCD1 as a novel tumor-specific target for therapy in patients with ATC and should be further investigated in a clinical setting.
authors: Departments of Cancer Biology (C.A.v.R., L.A.M., A.C., J.M., H.W.T., R.C.S., J.A.C.) and Hematology and Oncology (H.W.T.), and Division of Endocrinology and Metabolism (R.C.S.), Mayo Clinic, Jacksonville, Florida, 32224; The Mayo Clinic Graduate School (C.A.v.R.), Rochester, Minnesota 55905; and Conrad Prebys Center for Chemical Genomics (A.B.P.), Sanford-Burnham Medical Research Institute, La Jolla, California 92037.
authors: Christina A
authors: CA
authors: von Roemeling
authors: Laura A
authors: LA
authors: Marlow
authors: Anthony B
authors: AB
authors: Pinkerton
authors: Angela
authors: A
authors: Crist
authors: James
authors: J
authors: Miller
authors: Han W
authors: HW
authors: Tun
authors: Robert C
authors: RC
authors: Smallridge
authors: John A
authors: JA
authors: Copland
mesh_terms: D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism*; D065646:Thyroid Carcinoma, Anaplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D046888:Tissue Array Analysis
chemical_list: D013230:Stearoyl-CoA Desaturase