Aberrant lipid metabolism in anaplastic thyroid carcinoma reveals stearoyl CoA desaturase 1 as a novel therapeutic target

Christina A. Von Roemeling, Laura A. Marlow, Anthony B. Pinkerton, Angela Crist, James Miller, Han W Tun, Robert Christian Smallridge, John A III Copland

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Context: 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. Design: 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 reticulumassociated 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 tumorspecific target for therapy in patients with ATC and should be further investigated in a clinical setting.

Original languageEnglish (US)
Pages (from-to)E697-E709
JournalJournal of Clinical Endocrinology and Metabolism
Volume100
Issue number5
DOIs
StatePublished - May 1 2015

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Stearoyl-CoA Desaturase
Lipid Metabolism
Tumors
Cell Survival
Genes
Unfolded Protein Response
Cells
Neoplasms
Metabolism
Therapeutics
Fatty Acids
Thyroid Gland
Cell signaling
Cell Proliferation
Proteasome Inhibitors
Cell proliferation
Biomarkers
Cell death
Endoplasmic Reticulum Stress
Critical Pathways

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

Aberrant lipid metabolism in anaplastic thyroid carcinoma reveals stearoyl CoA desaturase 1 as a novel therapeutic target. / Von Roemeling, Christina A.; Marlow, Laura A.; Pinkerton, Anthony B.; Crist, Angela; Miller, James; Tun, Han W; Smallridge, Robert Christian; Copland, John A III.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 100, No. 5, 01.05.2015, p. E697-E709.

Research output: Contribution to journalArticle

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abstract = "Context: 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. Design: 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 reticulumassociated 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 tumorspecific target for therapy in patients with ATC and should be further investigated in a clinical setting.",
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