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. 2015 May;100(5):E697-709.
doi: 10.1210/jc.2014-2764. Epub 2015 Feb 12.

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

Christina A von Roemeling  1 , Laura A Marlow, Anthony B Pinkerton, Angela Crist, James Miller, Han W Tun, Robert C Smallridge, John A Copland
Affiliations

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

Christina A von Roemeling et al. J Clin Endocrinol Metab. 2015 May.

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 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.

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Figures

Figure 1.
Figure 1.
SCD1 expression profile in thyroid malignancy. A, Heat map of fatty acid metabolism in ATC vs normal thyroid patient tissue samples is shown. Black arrows indicate SCD1 and SCD5 expression. B, Results of QPCR for SCD1 mRNA levels in normal, FA, PTC, FTC, and ATC patient tissue samples expressed as fold change compared with Normal 1 patient, whose level is set to 1. C, IHC expression of SCD1 in normal, FA, PTC, FTC, and ATC patient tissues were quantitated using the H-score method as described in Materials and Methods. PTC and FTC samples are further sorted into noninvasive and invasive groups. Mean H-score ± SD is given. D, QPCR for SCD1 mRNA levels in normal, FA, PTC, FTC, and ATC patient-derived cells. Levels are normalized to mean normal expression, which was set at 1. E, Western blot analysis of SCD1 protein expression in normal, FA, PTC, FTC, and ATC patient-derived cells. β-Actin is shown to demonstrate equal protein loading.
Figure 2.
Figure 2.
Effects of pharmacological and genetic SCD1 inhibition in thyroid cells. A, Proliferative dose response of thyroid cells to the SCD1 small molecule inhibitor A939572 in normal thyroid cells, FA cells, PTC cells, FTC cells, and ATC cells. Proliferative dose response of ATC cells to the small molecule SCD1 inhibitor MF-438. Results are presented as percent cell number relative to DMSO-treated control. B, Western blot for SCD1 protein expression in NT control and target SCD1 (SCD780, SCD1200) lentivirus shRNA-infected cells. β-Actin is shown to demonstrate equal protein loading. C, Proliferation of NT vs target SCD1 knockdown cells. Results are presented as percent cell number relative to NT control. D, Summary bar graph of cell death analysis of NT and target SCD1 knockdown cells. *, P < .05 as compared with NT control cells.
Figure 3.
Figure 3.
SCD1 inhibitors induce ER stress in ATC cells. ATC cell proliferative rescue assay using exogenous OA in A939572- (A) and MF-438 (B)-treated cells. Control cells were treated with DMSO plus BSA. Results are presented as percent cell number relative to control. *, P < .05, monotherapy as compared with control; **, P < .05, monotherapy + OA as compared with monotherapy alone. C, QPCR for transcriptional up-regulation of UPR genes in ATC cells treated with A939572 ± 5 μM OA (A939 OA). Fold change was compared with DMSO control. D, Western blot for protein expression of PARP as well as the UPR genes CHOP and spliced XBP1 (sXBP1) in ATC cells treated with the IC50 values of A939572 ± 5 μM OA. β-Actin is shown to demonstrate equal protein loading. E, Immunofluorescence for expression of the ERAD marker HERPUD1 in ATC cells treated with the IC50 values of A939572 ± 5 μM OA. HERPUD1 demonstrates cytoplasmic localization. 4′,6′-Diamino-2-phenylindole was used as a nuclear marker.
Figure 4.
Figure 4.
SCD1 inhibitor induced ER stress and the UPR response in ATC cells. A, Proposed mechanism of combination therapy: A939572- or MF-438-mediated activation of the UPR through SCD1 inhibition prompts selective translation of ER stress response genes that drive prosurvival responses including decreased translation, ERAD, and chaperone-mediated protein refolding (highlighted in the green boxes). Targeted inhibition of ERAD using proteasome inhibitors such as bortezomib or carfilzomib is thought to further induce cellular stress, resulting in tumor cell apoptosis (red box). B, Monotherapeutic dose response of carfilzomib in ATC cells. IC50 values are listed. Combinatorial dose response of carfilzomib with A939572 (C) or MF-438 (E) in THJ29T and THJ16T cells are shown. D and F, Combination index values evaluating drug synergy generated using CalcuSyn software as described in the text in THJ29T and THJ16T cells. Car, carfilzomib; CI, combination index.
Figure 5.
Figure 5.
Evaluation of tumor cell viability in response to combinatorial therapy. Western blot for PARP cleavage and CHOP expression in THJ29T and THJ16T ATC cells treated with A939572 (A) or MF-438 (B) in combination with carfilzomib. β-Actin is shown to demonstrate equal protein loading. C, Cell death analysis using flow cytometry sorting of propidium iodide-stained cells treated with the IC50 dose of indicated drugs after a 48-hour treatment. Car, carfilzomib. Graphical results are shown in panel D. *, 5% or greater increase in cell death as compared with DMSO control; **, 5% or greater increase in cell death as compared with monotherapy.
Figure 6.
Figure 6.
Results of combinatorial therapy in an in vivo model of ATC. A, Mean THJ16T cell xenograft tumor volume of mice treated with MF-438 and carfilzomib independently or in combination. A treatment map depicting drug administration is included. B–G, Hematoxylin and eosin (H&E) staining as well as ki67 (proliferative index), cleaved caspase-3 (CC3; apoptosis marker), CD31 (endothelial cell marker), HERPUD1 (ER stress marker), and survivin (inhibitor of apoptosis, inhibitor of apoptosis family) was performed. Asterisks indicate statistically significant changes in IHC scores as compared with placebo control. P ≤ .05.
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