scholarly journals OR21-03 Determining Novel Therapeutic Targets Using an in Vitro Model of TRb Tumor Suppression in Anaplastic Thyroid Cancer

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Noelle E Gillis ◽  
Eric L Bolf ◽  
Cole Davidson ◽  
Lauren Cozzens ◽  
Jennifer Tomczak ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Tumor Suppressor ◽  
Cancer Cells ◽  
Cell Line ◽  
Cell Lines ◽  
Therapeutic Targets ◽  
Anaplastic Thyroid Cancer ◽  
Hormone Treatment ◽  
Novel Therapeutic

Abstract Anaplastic thyroid cancer (ATC) is one of the most lethal endocrine cancers, with an average survival time of six months after diagnosis. These aggressive tumors are characterized by rapid local extension, distant metastasis, and resistance to radioactive iodine therapy and mainstream chemotherapy. There are very limited treatment options for this aggressive form of thyroid cancer, highlighting a need for a deeper understanding of its mechanisms for development of more effective therapies. Loss of expression of the thyroid hormone receptor beta (TRβ) via epigenetic silencing is common amongst solid tumors, including ATC. Despite its recognized role as a tumor suppressor, the mechanisms underlying TRβ tumor suppressor activity remain uncharacterized. We previously created a stable ATC cell line with constitutive re-expression of TRβ (SW-TRβ). These stable cells exhibit a slower baseline growth rate than both the corresponding parental cell line (SW1736) and the stable empty vector control cell line (SW-EV). Since the effects of thyroid hormone treatment on the growth of cancer cells remain unclear, we investigated changes in growth rates of these cells in response to hormone treatment (triiodothyronine (T3) 10-8M). While T3 had no effect on SW-EV cells, the addition of hormone significantly slowed the growth of the SW-TRβ cells after two days. With longer exposure to T3 (five days), the SW-TRβ cells exhibited an apoptotic phenotype. We confirmed that the observed cell death was due to induction of apoptosis by assessing caspase 3 cleavage by immunoblot. The parental SW1736 cell line harbors a deleterious p53 truncating mutation, which is maintained in our stable cell lines. Therefore, we hypothesize that this T3-induced apoptosis is occurring through an alternate, p53-independent, signaling pathway. This prompted us to examine RNA-seq data obtained from these cell lines under similar conditions to identify potential regulators of this response. Interestingly, pathway analysis revealed decreased CDK4/6-mediated cell cycle progression and activation of JAK1/STAT1 signaling upon T3 treatment. These are novel mechanisms by which activation of T3-TRβ signaling can slow tumor growth and promote apoptosis in p53-deficient cancer cells. Furthermore, these pathways represent novel therapeutic targets specifically for ATC with potential high impact clinical applications.

scholarly journals Thyroid hormone receptor beta inhibits the PI3K-Akt-mTOR signaling axis in anaplastic thyroid cancer cell lines via genomic mechanisms

2021 ◽  
Author(s):  
Cole D Davidson ◽  
Eric L Bolf ◽  
Noelle E Gillis ◽  
Lauren M Cozzens ◽  
Jennifer A Tomczak ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Anaplastic Thyroid Cancer ◽  
Regulatory Subunit ◽  
Pi3k Signaling ◽  
Receptor Beta

Abstract Thyroid cancer is the most common endocrine malignancy, and the global incidence has increased rapidly over the past few decades. Anaplastic thyroid cancer (ATC) is highly aggressive, dedifferentiated, and patients have a median survival of fewer than six months. Oncogenic alterations in ATC include aberrant PI3K signaling through receptor tyrosine kinase (RTK) amplification, loss of phosphoinositide phosphatase expression and function, and Akt amplification. Furthermore, the loss of expression of the tumor suppressor thyroid hormone receptor beta (TRβ) is strongly associated with ATC. TRβ is known to suppress PI3K in follicular thyroid cancer and breast cancer by binding to the PI3K regulatory subunit p85⍺. However, the role of TRβ in suppressing PI3K signaling in ATC is not completely delineated. Here we report that TRβ indeed suppresses PI3K signaling in ATC cell lines through unreported genomic mechanisms including a decrease in RTK expression and increase in phosphoinositide and Akt phosphatase expression. Furthermore, the reintroduction and activation of TRβ in ATC cell lines enables an increase in the efficacy of the competitive PI3K inhibitors LY294002 and buparlisib on cell viability, migration, and suppression of PI3K signaling. These findings not only uncover additional tumor suppressor mechanisms of TRβ but shed light into the implication of TRβ status and activation on inhibitor efficacy in ATC tumors.

scholarly journals The Knockdown of Nrf2 Suppressed Tumor Growth and Increased the Sensitivity to Lenvatinib in Anaplastic Thyroid Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Zhongqin Gong ◽  
Lingbin Xue ◽  
Minghui Wei ◽  
Zhimin Liu ◽  
Alexander C. Vlantis ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Papillary Thyroid Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anaplastic Thyroid Cancer ◽  
Thyroid Cancer Cell ◽  
Papillary Thyroid ◽  
Thyroid Cancer Cells

Papillary thyroid cancer can dedifferentiate into a much more aggressive form of thyroid cancer, namely into anaplastic thyroid cancer. Nrf2 is commonly activated in papillary thyroid cancer, whereas its role in anaplastic thyroid cancer has not been fully explored. In this study, we used two cell lines and an animal model to examine the function of Nrf2 in anaplastic thyroid cancer. The role of Nrf2 in anaplastic thyroid cancer was investigated by a series of functional studies in two anaplastic thyroid cancer cell lines, FRO and KAT-18, and further confirmed with an in vivo study. The impact of Nrf2 on the sensitivity of anaplastic thyroid cancer cells to lenvatinib was also investigated to evaluate its potential clinical implication. We found that the expression of Nrf2 was significantly higher in anaplastic thyroid cancer cell line cells than in papillary thyroid cancer cells or normal control cells. Knockdown of Nrf2 in anaplastic thyroid cancer cells inhibited their viability and clonogenicity, reduced their migration and invasion ability in vitro, and suppressed their tumorigenicity in vivo. Mechanistically, knockdown of Nrf2 decreased the expression of Notch1. Lastly, knockdown of Nrf2 increased the sensitivity of anaplastic thyroid cancer cells to lenvatinib. As knockdown of Nrf2 reduced the metastatic and invasive ability of anaplastic thyroid cancer cells by inhibiting the Notch 1 signaling pathway and increased the cancer cell sensitivity to lenvatinib, Nrf2 could be a promising therapeutic target for patients with anaplastic thyroid cancer.

scholarly journals Thyroid hormone receptor beta inhibits the PI3K-Akt-mTOR signaling axis in anaplastic thyroid cancer via genomic mechanisms

2020 ◽  
Author(s):  
Cole D. Davidson ◽  
Eric L. Bolf ◽  
Noelle E. Gillis ◽  
Lauren M. Cozzens ◽  
Jennifer A. Tomczak ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Tumor Suppressor ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Anaplastic Thyroid Cancer ◽  
Regulatory Subunit ◽  
Pi3k Signaling ◽  
Phosphoinositide Phosphatase ◽  
Receptor Beta

AbstractThyroid cancer is the most common endocrine malignancy, and the global incidence has increased rapidly over the past few decades. Anaplastic thyroid cancer (ATC) is highly aggressive, dedifferentiated, and patients have a median survival of fewer than six months. Oncogenic alterations in ATC include aberrant PI3K signaling through receptor tyrosine kinase (RTK) amplification, loss of phosphoinositide phosphatase expression and function, and Akt amplification. Furthermore, the loss of expression of the tumor suppressor thyroid hormone receptor beta (TRβ) is strongly associated with ATC. TRβ is known to suppress PI3K in follicular thyroid cancer and breast cancer by binding to the PI3K regulatory subunit p85α. However, the role of TRβ in suppressing PI3K signaling in ATC is not completely delineated. Here we report that TRβ indeed suppresses PI3K signaling in ATC through unreported genomic mechanisms including a decrease in RTK expression and increase in phosphoinositide and Akt phosphatase expression. Furthermore, the reintroduction and activation of TRβ in ATC enables an increase in the efficacy of the competitive PI3K inhibitors LY294002 and buparlisib on cell viability, migration, and suppression of PI3K signaling. These findings not only uncover additional tumor suppressor mechanisms of TRβ but shed light into the implication of TRβ status and activation on inhibitor efficacy in ATC tumors.Abstract FigureGraphical abstract

scholarly journals Doxorubicin-Loaded Melanin Particles for Enhanced Chemotherapy in Drug-Resistant Anaplastic Thyroid Cancer Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Kun Wang ◽  
Shouju Wang ◽  
Kun Chen ◽  
Yijing Zhao ◽  
Xingqun Ma ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Thyroid Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Cellular Uptake ◽  
Therapeutic Efficacy ◽  
Anaplastic Thyroid Cancer ◽  
Drug Resistant ◽  
Melanin Nanoparticles ◽  
Thyroid Cancer Cells

Anaplastic thyroid cancer (ATC) is highly aggressive and tends to develop drug resistance to standard chemotherapies. To overcome the drug resistance of ATC, we synthesized dopamine-melanin nanoparticles (MNPs) loaded with doxorubicin (Dox) molecules. The Dox-loaded MNPs (Dox-MNPs) developed exhibited increased cellular uptake and enhanced therapeutic efficacy in drug-resistant ATC cell line HTh74R, compared with free Dox. The native MNPs were found to have excellent biocompatibility, which suggests that Dox-MNPs may have potential in the treatment of ATC.

scholarly journals A Thyroid Hormone Receptor Beta Specific Agonist Suppresses Anaplastic Thyroid Cancer Cell Phenotype and Increases Efficacy of Therapeutic Agents

2021 ◽  
Author(s):  
Noelle E Gillis ◽  
Cole D Davidson ◽  
Lauren M Cozzens ◽  
Emily R Wilson ◽  
Eric L Bolf ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Cell Lines ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Anaplastic Thyroid Cancer ◽  
Therapeutic Agents ◽  
Selective Activation ◽  
Aggressive Phenotype ◽  
Receptor Beta

Background: Anaplastic thyroid cancer (ATC) is one of the most lethal endocrine cancers, with an average survival time of six months after diagnosis. These aggressive tumors have very limited treatment options highlighting a need for a deeper understanding of its mechanisms for development of more effective therapies. We have previously shown that the liganded thyroid hormone receptor beta (TRβ) can function as a tumor suppressor and induce re-differentiation in ATC cells. We therefore tested the hypothesis that selective activation of TRβ with sobetirome (GC-1) could reduce the tumorigenic phenotypes of ATC cell lines and improve the efficacy of clinically relevant therapeutics. Methods: We used a panel of four ATC cell lines with variable genetic backgrounds to assess the ability of GC-1 to reduce the aggressive phenotype. The effects of GC-1 alone or in combination with buparlisib, alpelisib, sorafenib, and palbociclib on cell growth, viability, and migration were determined and compared with the gene expression levels of selected markers. The impact of these treatments on the cancer stem cell population was assessed by tumorsphere assay. Thyroid differentiation markers were measured by gene analysis, and sodium iodide symporter (NIS) protein level and function were determined. Results: Our results show that GC-1 alone can decrease cell viability, growth, and slow cell migration in all four ATC cell lines. In addition, GC-1 is able to further block each of these phenotypes when combined with buparlisib, alpelisib, sorafenib, or palbociclib. GC-1 alone blocks thyrosphere outgrowth in all cell lines and increases the efficacy of each of the therapeutic agents tested. GC-1 increased NIS transcript and protein levels to allow for increased iodide uptake in ATC cells. Conclusion: Activation of TRβ with selective agonist sobetirome (GC-1) reduces the aggressive phenotype and induced re-differentiation in ATC cells and increases the efficacy of therapeutic agents that are currently used in the treatment of ATC. These results indicate that selective activation of TRβ not only induces a tumor suppression program de novo but enhances the effectiveness of anti-cancer agents.

scholarly journals SAT-571 Restoration of Thyroid Hormone Receptor Beta Signaling Reprograms Anaplastic Thyroid Cancer Cells

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Noelle Gillis ◽  
Eric Bolf ◽  
Cole Davidson ◽  
Jennifer Tomczak ◽  
Seth Frietze ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Cancer Cells ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Anaplastic Thyroid Cancer ◽  
Thyroid Cancer Cells ◽  
Receptor Beta

scholarly journals Genomic complexity and targeted genes in anaplastic thyroid cancer cell lines

2017 ◽  
Vol 24 (5) ◽  
pp. 209-220 ◽  
Author(s):  
Eleanor L Woodward ◽  
Andrea Biloglav ◽  
Naveen Ravi ◽  
Minjun Yang ◽  
Lars Ekblad ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anaplastic Thyroid Cancer ◽  
Cancer Cell Lines ◽  
Fragile Sites ◽  
Thyroid Cancer Cell ◽  
Thyroid Cancer Cell Lines

Anaplastic thyroid cancer (ATC) is a highly malignant disease with a very short median survival time. Few studies have addressed the underlying somatic mutations, and the genomic landscape of ATC thus remains largely unknown. In the present study, we have ascertained copy number aberrations, gene fusions, gene expression patterns, and mutations in early-passage cells from ten newly established ATC cell lines using single nucleotide polymorphism (SNP) array analysis, RNA sequencing and whole exome sequencing. The ATC cell line genomes were highly complex and displayed signs of replicative stress and genomic instability, including massive aneuploidy and frequent breakpoints in the centromeric regions and in fragile sites. Loss of heterozygosity involving whole chromosomes was common, but there were no signs of previous near-haploidisation events or chromothripsis. A total of 21 fusion genes were detected, including six predicted in-frame fusions; none were recurrent. Global gene expression analysis showed 661 genes to be differentially expressed between ATC and papillary thyroid cancer cell lines, with pathway enrichment analyses showing downregulation of TP53 signalling as well as cell adhesion molecules in ATC. Besides previously known driver events, such as mutations in BRAF, NRAS, TP53 and the TERT promoter, we identified PTPRD and NEGR1 as putative novel target genes in ATC, based on deletions in six and four cell lines, respectively; the latter gene also carried a somatic mutation in one cell line. Taken together, our data provide novel insights into the tumourigenesis of ATC and may be used to identify new therapeutic targets.

scholarly journals Molecular Mechanisms of the Effects of Low Concentrations of Taxol in Anaplastic Thyroid Cancer Cells

Endocrinology ◽  
2004 ◽  
Vol 145 (7) ◽  
pp. 3143-3152 ◽  
Author(s):  
V. M. Pushkarev ◽  
D. V. Starenki ◽  
V. A. Saenko ◽  
H. Namba ◽  
J. Kurebayashi ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Biological Effects ◽  
Drug Effects ◽  
Anaplastic Thyroid Cancer ◽  
Membrane Asymmetry ◽  
Kinase Activation ◽  
Thyroid Cancer Cells

Abstract Understanding the detailed mechanisms of a chemotherapeutic agent action on cancer cells is essential for planning the clinical applications because drug effects are often tissue and cell type specific. This study set out to elucidate the molecular pathways of Taxol effects in human anaplastic thyroid cancer cells using as an experimental model four cell lines, ARO, KTC-2, KTC-3 (anaplastic thyroid cancer), and FRO (undifferentiated follicular cancer), and primary thyrocytes. All cell lines were sensitive to Taxol, although to different extent. In primary thyrocytes the drug displayed substantially lower cytotoxicity. In thyroid cancer cells, Taxol-induced changes characteristic to apoptosis such as poly (ADP-ribose) polymerase and procaspase cleavage and alteration of membrane asymmetry only within a narrow concentration range, from 6 to 50 nm. At higher concentration, other form(s) of cell death perhaps associated with mitochondrial collapse was observed. Low doses of Taxol enhanced Bcl2 phosphorylation and led to its degradation observed on the background of a sustained or increasing Bax level and accumulation of survivin and X-chromosome-linked inhibitor of apoptosis. c-jun-NH2 terminal kinase activation was essential for the apoptosis in anaplastic thyroid cancer cells, whereas Raf/MAPK kinase/ERK and phosphatidylinositol-3-OH kinase/Akt were likely to comprise main survival mechanisms. Our results suggest an importance of cautious interpreting of biological effects of Taxol in laboratory studies and for determining optimal doses of Taxol to achieve the desired therapeutic effect in anaplastic thyroid cancers.

Synthesis and Characterization of Quinoline-3-Carboxamide Derivatives as Inhibitors of the ATM Kinase

2020 ◽  
Vol 20 (23) ◽  
pp. 2070-2079
Author(s):  
Srimadhavi Ravi ◽  
Sugata Barui ◽  
Sivapriya Kirubakaran ◽  
Parul Duhan ◽  
Kaushik Bhowmik
Keyword(s):  
Western Blot ◽  
Cancer Cells ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Cancer Cell Lines ◽  
Atm Kinase ◽  
Cytotoxicity Studies

Background: The importance of inhibiting the kinases of the DDR pathway for radiosensitizing cancer cells is well established. Cancer cells exploit these kinases for their survival, which leads to the development of resistance towards DNA damaging therapeutics. Objective: In this article, the focus is on targeting the key mediator of the DDR pathway, the ATM kinase. A new set of quinoline-3-carboxamides, as potential inhibitors of ATM, is reported. Methods: Quinoline-3-carboxamide derivatives were synthesized and cytotoxicity assay was performed to analyze the effect of molecules on different cancer cell lines like HCT116, MDA-MB-468, and MDA-MB-231. Results: Three of the synthesized compounds showed promising cytotoxicity towards a selected set of cancer cell lines. Western Blot analysis was also performed by pre-treating the cells with quercetin, a known ATM upregulator, by causing DNA double-strand breaks. SAR studies suggested the importance of the electron-donating nature of the R group for the molecule to be toxic. Finally, Western-Blot analysis confirmed the down-regulation of ATM in the cells. Additionally, the PTEN negative cell line, MDA-MB-468, was more sensitive towards the compounds in comparison with the PTEN positive cell line, MDA-MB-231. Cytotoxicity studies against 293T cells showed that the compounds were at least three times less toxic when compared with HCT116. Conclusion: In conclusion, these experiments will lay the groundwork for the evolution of potent and selective ATM inhibitors for the radio- and chemo-sensitization of cancer cells.

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