Human Follicular Thyroid Cancer Cell Research Articles

Piperlongumine Induces Cellular Apoptosis and Autophagy via the ROS/Akt Signaling Pathway in Human Follicular Thyroid Cancer Cells.

Thyroid cancer (TC) is the most common endocrine malignancy. Recently, the global incidence of TC has increased rapidly. Differentiated thyroid cancer includes papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC), which are the most common types of TC. Although PTCs and FTCs exert good prognoses and high survival rates, FTCs tend to be more aggressive than PTCs. There is an urgent need to improve patient outcomes by developing effective therapeutic agents for FTCs. Piperlongumine exerts anti-cancer effects in various human carcinomas, including human anaplastic TCs and PTCs. However, the anti-cancer effects of piperlongumine in FTCs and the underlying mechanisms are yet to be elucidated. Therefore, in the present study, we evaluated the effect of piperlongumine on cell proliferation, cell cycle, apoptosis, and autophagy in FTC cells with flowcytometry and Western blot. We observed that piperlongumine caused growth inhibition, cell cycle arrest, apoptosis induction, and autophagy elevation in FTC cells. Activities of reactive oxygen species and the downstream PI3K/Akt pathway were the underlying mechanisms involved in piperlongumine mediated anti-FTC effects. Advancements in our understanding of the effects of piperlongumine in FTC hold promise for the development of novel therapeutic strategies.

The CellBox-2 Mission to the International Space Station: Thyroid Cancer Cells in Space

A spaceflight to the International Space Station (ISS) is a dream of many researchers. We had the chance to investigate the effect of real microgravity (CellBox-2 Space mission) on the transcriptome and proteome of FTC-133 human follicular thyroid cancer cells (TCC). The cells had been sent to the ISS by a Falcon 9 rocket of SpaceX CRS-13 from Cape Canaveral (United States) and cultured in six automated hardware units on the ISS before they were fixed and returned to Earth. Multicellular spheroids (MCS) were detectable in all spaceflight hardware units. The VCL, PXN, ITGB1, RELA, ERK1 and ERK2 mRNA levels were significantly downregulated after 5 days in space in adherently growing cells (AD) and MCS compared with ground controls (1g), whereas the MIK67 and SRC mRNA levels were both suppressed in MCS. By contrast, the ICAM1, COL1A1 and IL6 mRNA levels were significantly upregulated in AD cells compared with 1g and MCS. The protein secretion measured by multianalyte profiling technology and enzyme-linked immunosorbent assay (AngiogenesisMAP®, extracellular matrix proteins) was not significantly altered, with the exception of elevated angiopoietin 2. TCC in space formed MCS, and the response to microgravity was mainly anti-proliferative. We identified ERK/RELA as a major microgravity regulatory pathway.

Stromal interaction molecule 1 (STIM1) knock down attenuates invasion and proliferation and enhances the expression of thyroid-specific proteins in human follicular thyroid cancer cells

Stromal interaction molecule 1 (STIM1) and the ORAI1 calcium channel mediate store-operated calcium entry (SOCE) and regulate a multitude of cellular functions. The identity and function of these proteins in thyroid cancer remain elusive. We show that STIM1 and ORAI1 expression is elevated in thyroid cancer cell lines, compared to primary thyroid cells. Knock-down of STIM1 or ORAI1 attenuated SOCE, reduced invasion, and the expression of promigratory sphingosine 1-phosphate and vascular endothelial growth factor-2 receptors in thyroid cancer ML-1 cells. Cell proliferation was attenuated in these knock-down cells due to increased G1 phase of the cell cycle and enhanced expression of cyclin-dependent kinase inhibitory proteins p21 and p27. STIM1 protein was upregulated in thyroid cancer tissue, compared to normal tissue. Downregulation of STIM1 restored expression of thyroid stimulating hormone receptor, thyroid specific proteins and increased iodine uptake. STIM1 knockdown ML-1 cells were more susceptible to chemotherapeutic drugs, and significantly reduced tumor growth in Zebrafish. Furthermore, STIM1-siRNA-loaded mesoporous polydopamine nanoparticles attenuated invasion and proliferation of ML-1 cells. Taken together, our data suggest that STIM1 is a potential diagnostic and therapeutic target for treatment of thyroid cancer.

Downregulated miR-21 mediates matrine-induced apoptosis via the PTEN/Akt signaling pathway in FTC-133 human follicular thyroid cancer cells.

Matrine is an alkaloid extracted from the leguminous plant Sophora flavescens. Matrine has clinical effects in the treatment of tumors, including those in lung cancer, nasopharyngeal cancer and liver cancer. However, the effect of matrine on follicular thyroid cancer has not been reported. The aim of the present study was to investigate the effect of matrine on follicular thyroid cancer and its potential mechanism. FTC-133 follicular thyroid cancer cells were treated with different concentrations of matrine, and an MTT assay showed that matrine inhibited the growth of FTC-133 cells in a dose- and time-dependent manner with an IC50 value of 154.8 µM. Cell apoptosis was analyzed by flow cytometry and the results showed that matrine effectively induced the apoptosis of FTC-133 cells. The expression level of microRNA (miR)-21 was analyzed by reverse transcription-quantitative PCR (RT-qPCR) analysis, and the mRNA and protein expression levels of PTEN, Akt and phosphorylated (p)-Akt were detected by RT-qPCR analysis and western blotting, respectively. The expression of miR-21 was significantly downregulated, PTEN was upregulated at the mRNA and protein expression levels, and p-Akt was downregulated in the FTC-133 cells. The effects of miR-21 mimics and miR-21 inhibitor on the expression of miR-21, PTEN and Akt in FTC-133 cells, and the effect of miR-21 mimics/matrine on the expression of PTEN were also investigated. The results of the present study suggested that matrine inhibited the growth and induced apoptosis of FTC-133 cells via the miR-21/PTEN/Akt signaling pathway.

Thyroid cancer cells in space during the TEXUS-53 sounding rocket mission \u2013 The THYROID Project

Human follicular thyroid cancer cells (FTC-133) were sent to space via a sounding rocket during the TEXUS-53 mission to determine the impact of short-term microgravity on these cells. To enable cell culture and fixation in real microgravity, an automated experiment container (EC) was constructed. In order to ensure safe cell culture, cell-chambers consisting of polycarbonate (PC) material were used. They were highly biocompatible as proved by measuring cell survival using Annexin V flow cytometry. In the follow-up experiment, FTC-133 cells were sent to space via a sounding rocket and were fixed before and after the microgravity (µg) phase with RNAlater. In addition, cells were tested for reactions on hypergravity (hyper-g) as much as 18 g to determine whether worst case acceleration during launch can have an influence on the cells. We investigated genes belonging to biological processes such as cytoskeleton, cell adhesion, tumor growth, angiogenesis and apoptosis. Pathway analyses revealed central functions of VEGFA and EGF. EGF upregulates aspartate beta-hydroxylase (ASPH) which is influencing CASP3. Hyper-g induced a significant up-regulation of TUBB1, VIM, RDX, CAV1, VEGFA and BCL2. FTC-133 cells grown in an automated EC exposed to µg revealed moderate gene expression changes indicating their survival in orbit.

Proteome Analysis of Human Follicular Thyroid Cancer Cells Exposed to the Random Positioning Machine

Several years ago, we detected the formation of multicellular spheroids in experiments with human thyroid cancer cells cultured on the Random Positioning Machine (RPM), a ground-based model to simulate microgravity by continuously changing the orientation of samples. Since then, we have studied cellular mechanisms triggering the cells to leave a monolayer and aggregate to spheroids. Our work focused on spheroid-related changes in gene expression patterns, in protein concentrations, and in factors secreted to the culture supernatant during the period when growth is altered. We detected that factors inducing angiogenesis, the composition of integrins, the density of the cell monolayer exposed to microgravity, the enhanced production of caveolin-1, and the nuclear factor kappa B p65 could play a role during spheroid formation in thyroid cancer cells. In this study, we performed a deep proteome analysis on FTC-133 thyroid cancer cells cultured under conditions designed to encourage or discourage spheroid formation. The experiments revealed more than 5900 proteins. Their evaluation confirmed and explained the observations mentioned above. In addition, we learned that FTC-133 cells growing in monolayers or in spheroids after RPM-exposure incorporate vinculin, paxillin, focal adhesion kinase 1, and adenine diphosphate (ADP)-ribosylation factor 6 in different ways into the focal adhesion complex.

Pathways Regulating Spheroid Formation of Human Follicular Thyroid Cancer Cells under Simulated Microgravity Conditions: A Genetic Approach.

Microgravity induces three-dimensional (3D) growth in numerous cell types. Despite substantial efforts to clarify the underlying mechanisms for spheroid formation, the precise molecular pathways are still not known. The principal aim of this paper is to compare static 1g-control cells with spheroid forming (MCS) and spheroid non-forming (AD) thyroid cancer cells cultured in the same flask under simulated microgravity conditions. We investigated the morphology and gene expression patterns in human follicular thyroid cancer cells (UCLA RO82-W-1 cell line) after a 24 h-exposure on the Random Positioning Machine (RPM) and focused on 3D growth signaling processes. After 24 h, spheroid formation was observed in RPM-cultures together with alterations in the F-actin cytoskeleton. qPCR indicated more changes in gene expression in MCS than in AD cells. Of the 24 genes analyzed VEGFA, VEGFD, MSN, and MMP3 were upregulated in MCS compared to 1g-controls, whereas ACTB, ACTA2, KRT8, TUBB, EZR, RDX, PRKCA, CAV1, MMP9, PAI1, CTGF, MCP1 were downregulated. A pathway analysis revealed that the upregulated genes code for proteins, which promote 3D growth (angiogenesis) and prevent excessive accumulation of extracellular proteins, while genes coding for structural proteins are downregulated. Pathways regulating the strength/rigidity of cytoskeletal proteins, the amount of extracellular proteins, and 3D growth may be involved in MCS formation.

Characterization of human follicular thyroid cancer cell lines in preclinical mouse models.

Follicular thyroid cancer (FTC) is the second most common type of thyroid cancers. In order to develop more effective personalized therapies, it is necessary to thoroughly evaluate patient-derived cell lines in in vivo preclinical models before using them to test new, targeted therapies. This study evaluates the tumorigenic and metastatic potential of a panel of three human FTC cell lines (WRO, FTC-238, and TT1609-CO2) with defined genetic mutations in two in vivo murine models: an orthotopic thyroid cancer model to study tumor progression and a tail vein injection model to study metastasis. All cell lines developed tumors in the orthotopic model, with take rates of 100%. Notably, WRO-derived tumors grew two to four times faster than tumors arising from the FTC-238 and TT2609-CO2 cell lines. These results mirrored those of a tail vein injection model for lung metastasis: one hundred percent of mice injected with WRO cells in the tail vein exhibited aggressive growth of bilateral lung metastases within 35 days. In contrast, tail vein injection of FTC-238 or TT2609-CO2 cells did not result in lung metastasis. Together, our work demonstrates that these human FTC cell lines display highly varied tumorigenic and metastatic potential in vivo with WRO being the most aggressive cell line in both orthotopic and lung metastasis models. This information will be valuable when selecting cell lines for preclinical drug testing.

Klotho inhibits human follicular thyroid cancer cell growth and promotes apoptosis through regulation of the expression of stanniocalcin-1.

The new anti-aging gene Klotho has been identified as a multi-functional humoral factor which influences multiple biological processes, including tumor progression. Although ample evidence indicates that Klotho plays important roles in cervical, lung and breast cancer, the role and mechanism of Klotho in thyroid cancer are still unclear. The present study aimed to investigate the effects and mechanisms of Klotho in human thyroid cancer cell lines FTC133 and FTC238. Klotho overexpression markedly reduced thyroid cancer FTC133 and FTC238 cell proliferation and enhanced apoptosis, whereas, Klotho silencing in the FTC133 and FTC238 cells increased cell growth. Moreover, soluble human KL1 (sKL) and Klotho overexpression had a similar effect on FTC133 and FTC238 cell growth. A high level of Klotho was also found to be associated with a low level of stanniocalcin 1 (STC1) in both the FTC133 and FTC238 cell lines. STC1 silencing significantly inhibited thyroid cancer cell proliferation, whereas recombinant human STC1 (hSTC1) markedly enhanced cell proliferation. In addition, our study demonstrated that hSTC1 treatment attenuated Klotho-induced inhibition of cell proliferation and promotion of apoptosis. Our data revealed the existence of a moderating effect between Klotho and STC1, where Klotho may inhibit thyroid tumor progression by inhibiting the tumor marker level of STC1.

Inhibition of Tumorigenesis by the Thyroid Hormone Receptor β in Xenograft Models

Previous studies showed a close association between several types of human cancers and somatic mutations of thyroid hormone receptor β (TRβ) and reduced expression of TRβ due to epigenetic inactivation and/or deletion of the THRB gene. These observations suggest that TRβ could act as a tumor suppressor in carcinogenesis. However, the mechanisms by which TRβ could function to inhibit tumorigenesis are less well understood. We used the human follicular thyroid cancer cell lines (FTC-133 and FTC-236 cells) to elucidate how functional expression of the THRB gene could affect tumorigenesis. We stably expressed the THRB gene in FTC cells and evaluated the effects of the expressed TRβ on cancer cell proliferation, migration, and tumor growth in cell-based studies and xenograft models. Expression of TRβ in FTC-133 cells, as compared with control FTC cells without TRβ, reduced cancer cell proliferation and impeded migration of tumor cells through inhibition of the AKT-mTOR-p70 S6K pathway. TRβ expression in FTC-133 and FTC-236 led to less tumor growth in xenograft models. Importantly, new vessel formation was significantly suppressed in tumors induced by FTC cells expressing TRβ compared with control FTC cells without TRβ. The decrease in vessel formation was mediated by the downregulation of vascular endothelial growth factor in FTC cells expressing TRβ. These findings indicate that TRβ acts as a tumor suppressor through downregulation of the AKT-mTOR-p70 S6K pathway and decreased vascular endothelial growth factor expression in FTC cells. The present results raise the possibility that TRβ could be considered as a potential therapeutic target for thyroid cancer.

Spheroid formation of human thyroid cancer cells in an automated culturing system during the Shenzhou-8 Space mission

Human follicular thyroid cancer cells were cultured in Space to investigate the impact of microgravity on 3D growth. For this purpose, we designed and constructed a cell container that can endure enhanced physical forces, is connected to fluid storage chambers, performs media changes and cell harvesting automatically and supports cell viability. The container consists of a cell suspension chamber, two reserve tanks for medium and fixative and a pump for fluid exchange. The selected materials proved durable, non-cytotoxic, and did not inactivate RNAlater. This container was operated automatically during the unmanned Shenzhou-8 Space mission. FTC-133 human follicular thyroid cancer cells were cultured in Space for 10 days. Culture medium was exchanged after 5 days in Space and the cells were fixed after 10 days. The experiment revealed a scaffold-free formation of extraordinary large three-dimensional aggregates by thyroid cancer cells with altered expression of EGF and CTGF genes under real microgravity.

Autophagy induction of reversine on human follicular thyroid cancer cells

The incurable differentiated thyroid cancer (DTC), poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are the most aggressive in all of the thyroid cancers. Unfortunately, there are almost no effective therapies. A novel and effective treatment is urgently needed to develop. Recently, reversine, a small synthetic purine analogue, has been reported to be effective in human thyroid cancer suppression through cell cycle arrest and apoptosis induction. In this study, we performed an in vitro evaluation of reversine on autophagy activation, one of the programmed cell death, and the related mechanisms in human follicular thyroid cancer cell line WRO. Incubation of WRO cells with reversine induced autophagosome formation in a short time treatment. LC3-II overexpression in a dosage-dependent manner with reversine treatment was demonstrated in the autophagy activation. Moreover, reversine suppressed Akt/mTOR related signaling pathway activation, a major pathway for autophagy activation, was also revealed in WRO cells. Our data demonstrated that reversine is effective to induce autophagy. Moreover, the LC3-II overexpression and the p62 protein were degraded in a time-dependent manner, indicating that the autophagic flux has happened in the reversine treated WRO cells. In addition, the activation of Akt/mTOR/p70S6K related pathways were shown to be reduced, suggesting these pathways may involve in the reversine mediated autophagy induction. Reversine is therefore worthy of further investigation in clinical therapeutics.

FUTURE STRATEGIES IN THE TREATMENT OF AGGRESSIVE THYROID CANCER

Radioiodine-refractory and anaplastic thyroid cancers have a poor prognosis that may not be significantly altered by the current treatment regimens. Therefore there is a compelling need to identify potential new therapies. TNF-related apoptosis inducing ligand (TRAIL) induces apoptosis selectively in tumor cells, the IG20/MADD (Insulinoma-Glucagonoma), a novel human gene, is over-expressed in cancer and confers TRAIL resistance. Therefore, we aimed to investigate the effects of IG20/MADD knockdown on TRAIL induced-apoptosis in different types of thyroid cancer. Material and Methods. A shRNA expressing lentivirus was used to selectively knockdown IG20/MADD in the human papillary thyroid cancer (PTC) cell lines: TPC1, KTC1 and BCPAP, the human follicular thyroid cancer (FTC) cell lines: WRO and FTC133 and the human anaplastic thyroid cancer (ATC): C643, CAL62 and HTh7. Apoptosis was assessed by propidium iodide or TMRM staining or detection of activated caspase-3 by flow-cytometry. Results. TPC1, BCPAP, WRO, C643, CAL62 and HTh7 cells were sensitive to TRAIL-induced apoptosis, while KTC1, FTC133, FRO and 8505C cells were resistant to even high dose of TRAIL (100 ng/ml). Upon knockdown of IG20/MADD all the sensitive cell lines cells had increased susceptibility to TRAIL-induced apoptosis and previously resistant 8505C and FTC133 cells became sensitive to TRAIL. Only FRO cells could not be rescued from TRAIL resistance because of caspase 8 deficiency, which is not a common finding in in vivo thyroid tumors. Moreover, the combination of TRAIL with select Akt/mTOR (perifosine and everolimus) and/or MEK inhibitors (PD-0325901) showed an antagonistic effect on TRAIL-induced apoptosis in ATC C643 cells, but had no effect on ATC 8505C cells. Conclusions. IG20/MADD knockdown in TRAIL treated thyroid cancer cells enhanced apoptosis in sensitive cells and induced significant cytotoxicity in resistant cells. This effect was not enhanced significantly in the presence of various inhibitors of the MAPK/PI3K/Akt signaling pathways. TRAIL treatment combined with IG20/MADD knockdown may be a potential therapeutic modality for radioiodine-refractory and anaplastic thyroid cancer.

Reversine, a 2,6-disubstituted Purine, as an Anti-cancer Agent in Differentiated and Undifferentiated Thyroid Cancer Cells

A novel and effective treatment is urgently needed to deal with the current treatment dilemma in incurable differentiated thyroid cancer (DTC), poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC). Reversine, a small synthetic purine analogue (2,6-disubstituted purine), has been shown to be effective in tumor suppression. We performed in vitro evaluation of anti-tumor effects of reversine on proliferation, cell cycle, and apoptosis in human PDTC, ATC, and follicular thyroid cancer cell lines, respectively. Treatment of these three lines with reversine inhibited proliferation in a time- and dose-dependent manner. G2/M accumulation was demonstrated in cell cycle analysis. Reversine induced apoptosis in PDTC cells with caspase-3 and caspase-8 activation, but not caspase-9. Use of a pan-caspase inhibitor before treatment with reversine attenuated cell death. Reversine also showed in vivo growth inhibitory effects on ATC cells in a xenograft nude mice model. Data demonstrated that reversine is effective in inhibiting the growth of thyroid cancer cells by cell cycle arrest or apoptosis, especially with the more aggressive ATC and PDTC. Apoptosis was induced by the mitochondria-independent pathway. Reversine is therefore worthy of further investigation in clinical therapeutics.

Modulation of matrix metalloproteinase activity in human thyroid cancer cell lines using demethylating agents and histone deacetylase inhibitors

The purpose of this study was to investigate the effects of treating human thyroid cancer cell lines with demethylating agents and histone deacetylase (HDAC) inhibitors to see if they would downregulate expression and activity of the matrix metalloproteinases (MMP)-2 and MMP-9, resulting in inhibition of growth and invasion. A total of 1 papillary cancer cell line (TPC-1) and 3 follicular thyroid cancer cell lines (FTC-133, FTC-236, and FTC-238) were treated with the demethylating agent 5-azacytidine (5-AZC) and the HDAC inhibitors trichostatin A (TSA) and valproic acid (VA). The activity of MMP proteins was determined using gelatin zymography, and commercially available assays were used to quantify growth inhibition and thyroid cancer cell invasion. Treatment with TSA and VA resulted in decreased protein activity of MMP-2 and MMP-9 in all cell lines in a dose-dependent manner after 48 hours of treatment compared with untreated controls. In addition, 5-, TSA, and VA caused inhibition of growth in the range of 25-80% for all cell lines at 24, 48, and 72 hours. VA and TSA significantly decreased cell invasion in the FTC-133 and TPC-1 cell lines. The HDAC inhibitors TSA and VA decreased the protein activity of MMP-2 and MMP-9 and, in combination with the demethylating agent 5-AZC, inhibited cellular growth in human papillary and follicular thyroid cancer cell lines. These results elucidate our understanding of the pathways affected by the demethylating agents and HDAC inhibitors, and provide further evidence that MMPs are a potentially useful target for molecular therapies in patients with aggressive or refractory thyroid cancers.

Insulin glargine and insulin have identical effects on proliferation and phosphatidylinositol 3-kinase/AKT signalling in rat thyrocytes and human follicular thyroid cancer cells

Keywords Insulinglargine.Phosphatidylinositol3-kinase/AKTcascade.Proliferation.ThyroidcancerAbbreviationsFOXO Forkhead box OFRTL-5 Fisher rat thyroid low serum 5% (cells)PTEN Phosphatase and tensin homologueTo the Editor: The mitogenic potency of the analogousinsulin glargine (A21Gly,B31Arg,B32Arg human insulin)is currently under heated debate [1], since several clinicalstudies have raised the possibility of insulin glarginetreatment having a carcinogenic potential, especially inbreast cancer [2]. Moreover, latest data from Shukla et al.[3] suggest that insulin glargine may indeed trigger cellularproliferation in MCF-7 breast cancer cells at lower dosagesthan normal insulin.In the past years, the insulin/phosphatidylinositol3-kinase (PI3K)/protein kinase B (AKT) signalling cascadehas emerged as a central mediator of thyroid carcinogenesis[4]. Our group recently observed that PI3K/AKT mediatedinactivation of the tumour suppressor forkhead box O(FOXO) 3 is a hallmark of follicular and papillary thyroidcarcinogenesis [5]. Physiologically, FOXO3 accumulates inthe nucleus, where it controls the transcription of anti-proliferative and pro-apoptotic targets such as growth arrestand DNA-damage-inducible-protein 45 (GADD45), cylin-dependent kinase inhibitor 1B (p27

Resveratrol-Induced Notch Activation Potentially Mediates Autophagy in Human Follicular Thyroid Cancer Cells

Resveratrol-Induced Notch Activation Potentially Mediates Autophagy in Human Follicular Thyroid Cancer Cells

546 POSTER Gl261 brain tumor cells: responses to single or fractionated x-irradiation with the avb3 integrin thyroxine receptor antagonist TETRAC (tetraiodothyroacetic acid)

Thyroid hormone (l-thyroxine, T4, or 3,5,3′-triiodo-l-thyronine, T3) treatment of human papillary and follicular thyroid cancer cell lines resulted in enhanced cell proliferation, measured by proliferating cell nuclear antigen (PCNA). Thyroid hormone also induced activation of the Ras/MAPK (ERK1/2) signal transduction pathway. ERK1/2 activation and cell proliferation caused by thyroid hormone were blocked by an iodothyronine analogue, tetraiodothyroacetic acid (tetrac), that inhibits binding of iodothyronines to the cell surface receptor for thyroid hormone on integrin alphaVbeta3. A MAPK cascade inhibitor at MEK, PD 98059, also blocked hormone-induced cell proliferation. We then assessed the possibility that thyroid hormone is anti-apoptotic. We first established that resveratrol (10 μM), a pro-apoptotic agent in other cancer cells, induced p53-dependent apoptosis and c-fos, c-jun and p21 gene expression in both papillary and follicular thyroid cancer cells. Induction of apoptosis by the stilbene required Ser-15 phosphorylation of p53. Resveratrol-induced gene expression and apoptosis were inhibited more than 50% by physiological concentrations of T4. T4 activated MAPK in the absence of resveratrol, caused minimal Ser-15 phosphorylation of p53 and did not affect c-fos, c-jun and p21 mRNA abundance. Thus, plasma membrane-initiated activation of the MAPK cascade by thyroid hormone promotes papillary and follicular thyroid cancer cell proliferation in vitro.

RETRACTED: Thyroid hormone is a MAPK-dependent growth factor for thyroid cancer cells and is anti-apoptotic

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. Steroids has retracted this article because of image duplication. Aspects of the image in Figure 7B of this article have been confirmed to be a duplicate of an image (labelled Figure 8B) which appeared in an article titled: ‘Resveratrol Induces Apoptosis in Thyroid Cancer Cell Lines via a MAPK- and p53-Dependent Mechanism’, published in JCEM, Volume 87, Issue 3, 1 March 2002, pages 1223-1232, https://doi.org/10.1210/jcem.87.3.8345. Steroids can not confirm the authenticity of the image provided in this manuscript.

Induction of apoptosis in human follicular thyroid cancer cells by the histone deacetylase inhibitors TSA and FK228

Abstract Introduction: The histone deacetylase (HDAC) inhibitors are a heterogeneous group of compounds that alter the chromatin structure of neoplastic cells, causing cell-cycle arrest, redifferentiation, and apoptosis. TSA and FK228 are structurally different HDAC inhibitors that have been used for the treatment of several cancers in laboratory and clinical trials. The effects of TSA and FK228 on apoptosis have not been fully characterized or quantitated. We studied the effects of TSA and FK228 on apoptosis in a human follicular thyroid cancer cell line (FTC-236). Methods: We treated FTC-236 cells with TSA (25–100 ng/ml) and FK228 (0.1–1 ng/ml). Apoptosis was measured at 24 and 48 hours after treatment using annexin V-FITC labeling and flow cytometry. RNA was extracted at 24 and 48 hours and real-time PCR was performed to measure gene expression levels of bcl-2 and bcl-xl, two pro-survival proteins that function in the regulation of apoptosis. Results: At 48 hours after treatment, 6.4% of TSA-treated FTC-236 cells underwent apoptosis; 25.7% of FK228-treated cells underwent apoptosis in the same time period (p Conclusions: TSA and FK228 have differing effects on apoptosis and pro-survival gene expression in FTC-236 cells. A better understanding of the effects of HDAC inhibitors on apoptosis will allow clinicians to design treatment regimens based on the genetic profiles and tumor behavior of the targeted malignancies.