scholarly journals Inhibition of gap junction transfer sensitizes thyroid cancer cells to anoikis

2011 ◽  
Vol 18 (5) ◽  
pp. 613-626 ◽  
Author(s):  
Kirk Jensen ◽  
Aneeta Patel ◽  
Joanna Klubo-Gwiezdzinska ◽  
Andrew Bauer ◽  
Vasyl Vasko
Keyword(s):  
Thyroid Cancer ◽  
Gap Junction ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Thyroid Tissue ◽  
Human Thyroid ◽  
Thyroid Cancer Cell ◽  
Gap Junctional ◽  
Thyroid Cancer Cells

Resistance to anoikis (matrix deprivation-induced apoptosis) is a critical component of the metastatic cascade. Molecular mechanisms underlying resistance to anoikis have not been reported in thyroid cancer cells. For an in vitro model of anoikis, we cultured follicular, papillary, and anaplastic thyroid cancer cell lines on poly-HEMA-treated low-adherent plates. We also performed immunohistochemical analysis of human cancer cells that had infiltrated blood and/or lymphatic vessels. Matrix deprivation was associated with establishment of contacts between floating thyroid cancer cells and formation of multi-cellular spheroids. This process was associated with activation of gap junctional transfer. Increased expression of the gap junction molecule Connexin43 was found in papillary and anaplastic cancer cells forming spheroids. All non-adherent cancer cells showed a lower proliferation rate compared with adherent cells but were more resistant to serum deprivation. AKT was constitutively activated in cancer cells forming spheroids. Inhibition of gap junctional transfer through Connexin43 silencing, or by treatment with the gap junction disruptor carbenoxolone, resulted in loss of pAKT and induction of apoptosis in a cell-type-specific manner. In human thyroid tissue, cancer cells that had infiltrated blood vessels showed morphological similarity to cancer cells forming spheroids in vitro. Intra-vascular cancer cells demonstrated prominent AKT activation in papillary and follicular cancers. Increased Connexin43 immunoreactivity was observed only in intra-vascular papillary cancer cells. Our data demonstrate that establishment of inter-cellular communication contributes to thyroid cancer cell resistance to anoikis. These findings suggest that disruption of gap junctional transfer could represent a potential therapeutic strategy for prevention of metastases.

scholarly journals Induction of apoptosis and necrosis by zinc in human thyroid cancer cell lines

2001 ◽  
Vol 169 (2) ◽  
pp. 417-424 ◽  
Author(s):  
M Iitaka ◽  
S Kakinuma ◽  
S Fujimaki ◽  
I Oosuga ◽  
T Fujita ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Human Thyroid ◽  
Dependent Manner ◽  
Thyroid Cancer Cell ◽  
Thyroid Cancer Cell Lines ◽  
Thyroid Cancer Cells

Zinc at concentrations of 150, microM or higher induced necrosis as well as apoptosis in thyroid cancer cell lines. Necrosis was induced by zinc in a dose-dependent manner, whereas apoptosis did not increase at higher concentrations of zinc. The expression of the antiapoptotic protein phosphorylated Bad was markedly increased, whereas the expression of the proapoptotic proteins Bax and Bad decreased following Zn(2+) exposure. Zn(2+) induced rapid degradation of IkappaB, and an increase in the binding of nuclear transcription factor-kappaB (NF-kappaB). These observations indicate that antiapoptotic pathways were activated in thyroid cancer cells following exposure to Zn(2+). This may be a self-defence mechanism against apoptosis and may underlie the general resistance of thyroid cancer cells to apoptotic stimuli. Zinc may be a potential cytotoxic agent for the treatment of thyroid cancer.

scholarly journals Chlorotoxin Conjugated with Saporin Reduces Viability of ML-1 Thyroid Cancer Cells In Vitro

2019 ◽  
Author(s):  
Husref Rizvanovic ◽  
A Daniel Pinheiro ◽  
Kyoungtae Kim ◽  
Johnson Thomas
Keyword(s):  
Thyroid Cancer ◽  
Cell Viability ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Unmet Need ◽  
Matrix Metalloproteinase 2 ◽  
Dependent Manner ◽  
Thyroid Cancer Cell ◽  
Thyroid Cancer Cells

AbstractBackgroundAlthough differentiated thyroid cancer has good prognosis, radioactive iodine (RAI) resistant thyroid cancer is difficult to treat. Current therapies for progressive RAI resistant thyroid cancer are not very effective. There is an unmet need for better therapeutic agents in this scenario. Studies have shown that aggressive thyroid cancers express matrix metalloproteinase −2 (MMP-2). Chlorotoxin is a selective MMP-2 agonist. Given that Saporin is a well-known ribosome-inactivating protein used for anti-cancer treatment, we hypothesized that Chlorotoxin-conjugated Saporin (CTX-SAP) would inhibit the growth of aggressive thyroid cancer cell lines expressing MMP-2.MethodsThe ML-1 thyroid cancer cell line was used for this study because it is known to express MMP-2. ML-1 cells were treated with a toxin consisting of biotinylated Chlorotoxin bonded with a secondary conjugate of Streptavidin-ZAP containing Saporin (CTX-SAP) from 0 to 600 nM for 72 hours. Then, cell viability was measured via XTT assay at an absorbance of A450-630. Control experiments were set up using Chlorotoxin and Saporin individually at the same varying concentrations.ResultsAfter 7 hours of incubation, there was a statistically significant reduction in cell viability with increasing concentrations of the CTX-SAP conjugate (F=4.286, p=0.0057). In particular, the cell viability of ML-1 cells was decreased by 49.77% with the treatment of 600 nM of CTX-SAP (F=44.24), and the reduction in cell viability was statistically significant (Dunnett’s test p<0.0001). In contrast, individual Chlorotoxin or Saporin in increasing concentrations had no significant effect on cell viability using similar assay.ConclusionThis in vitro study demonstrated the efficacy of a CTX-SAP conjugate in reducing the viability of ML-1 thyroid cancer cells in a dose dependent manner. Further studies are needed to delineate the effectiveness of CTX-SAP in the treatment of aggressive thyroid cancer. Our study points towards MMP-2 as a potential target for RAI-resistant thyroid cancer.

scholarly journals The TUSC2 Tumour Suppressor Inhibits the Malignant Phenotype of Human Thyroid Cancer Cells via SMAC/DIABLO Protein

2020 ◽  
Vol 21 (3) ◽  
pp. 702
Author(s):  
Raffaela Mariarosaria Mariniello ◽  
Francesca Maria Orlandella ◽  
Anna Elisa De Stefano ◽  
Paola Lucia Chiara Iervolino ◽  
Giovanni Smaldone ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Carcinoma ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Biological Effects ◽  
Tumour Suppressor ◽  
Human Thyroid ◽  
Migration And Invasion ◽  
Thyroid Cancer Cell ◽  
Thyroid Cancer Cells

Thyroid carcinoma is the most common endocrine cancer and includes different forms. Among these, anaplastic thyroid carcinoma (ATC) is the rarest but the most lethal subtype, compared to papillary thyroid carcinoma (PTC) which shows an overall good prognosis. We have previously showed that Tumor Suppressor Candidate 2 (TUSC2), a known tumour suppressor gene, is downregulated in human PTC and ATC compared to normal thyroid samples. The aim of this study was to gain insight into the molecular mechanisms induced by TUSC2 in thyroid cancer cells. Here, we stably transfected TUSC2 in papillary (TPC-1) and in anaplastic (8505C) thyroid cancer cell lines and studied its effects on several biological processes, demonstrating that TUSC2 overexpression decreased thyroid cancer cell proliferation, migration and invasion. Through the proteome profiler apoptosis array, we observed that TUSC2 increased sensitivity to apoptosis by increasing the SMAC/DIABLO and CYTOCHROME C proteins. On the other hand, transient silencing of TUSC2, by siRNA, in an immortalized thyroid follicular epithelial cell line (Nthy-ori 3-1) showed the opposite effect. Finally modulation of SMAC/DIABLO partially rescued the biological effects of TUSC2. Thus, our data highlight a tumour suppressor role of TUSC2 in thyroid carcinogenesis, suggesting that it could be a promising target and biomarker for thyroid carcinoma.

scholarly journals 5-Aza-2′-Deoxycytidine Has Minor Effects on Differentiation in Human Thyroid Cancer Cell Lines, But Modulates Genes That Are Involved in Adaptation In Vitro

Thyroid ◽  
2013 ◽  
Vol 23 (3) ◽  
pp. 317-328 ◽  
Author(s):  
Geneviève Dom ◽  
Vanessa Chico Galdo ◽  
Maxime Tarabichi ◽  
Gil Tomás ◽  
Aline Hébrant ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Human Thyroid ◽  
Thyroid Cancer Cell ◽  
Thyroid Cancer Cell Lines

scholarly journals Interplay between thyroid cancer cells and macrophages: effects on IL-32 mediated cell death and thyroid cancer cell migration

2019 ◽  
Vol 42 (5) ◽  
pp. 691-703 ◽  
Author(s):  
Yvette J. E. Sloot ◽  
Katrin Rabold ◽  
Thomas Ulas ◽  
Dennis M. De Graaf ◽  
Bas Heinhuis ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Migration ◽  
Thyroid Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Cell Migration ◽  
Thyroid Cancer Cell ◽  
Thyroid Cancer Cells

scholarly journals Selumetinib Activity in Thyroid Cancer Cells: Modulation of Sodium Iodide Symporter and Associated miRNAs

2018 ◽  
Vol 19 (7) ◽  
pp. 2077 ◽  
Author(s):  
Sabine Wächter ◽  
Annette Wunderlich ◽  
Brandon Greene ◽  
Silvia Roth ◽  
Moritz Elxnat ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Sodium Iodide ◽  
Thyroid Cancer Cell ◽  
Sodium Iodide Symporter ◽  
Radioiodine Uptake ◽  
Thyroid Cancer Cell Lines ◽  
Thyroid Cancer Cells

Background: The MEK (mitogen-activated protein kinase)–inhibitor selumetinib led to increased radioiodine uptake and retention in a subgroup of patients suffering from radioiodine refractory differentiated thyroid cancer (RR-DTC). We aimed to analyse the effect of selumetinib on the expression of sodium iodide symporter (NIS; SLC5A5) and associated miRNAs in thyroid cancer cells. Methods: Cytotoxicity was assessed by viability assay in TPC1, BCPAP, C643 and 8505C thyroid cancer cell lines. NIS, hsa-let-7f-5p, hsa-miR-146b-5p, and hsa-miR-146b-3p expression was determined by quantitative RT-PCR. NIS protein was detected by Western blot. Radioiodine uptake was performed with a Gamma counter. Results: Selumetinib caused a significant reduction of cell viability in all thyroid cancer cell lines. NIS transcript was restored by selumetinib in all cell lines. Its protein level was found up-regulated in TPC1 and BCPAP cells and down-regulated in C643 and 8505C cells after treatment with selumetinib. Treatment with selumetinib caused a down-regulation of hsa-let-7f-5p, hsa-miR-146b-5p and hsa-miR-146b-3p in TPC1 and BCPAP cells. In 8505C cells, a stable or down-regulated hsa-miR-146b-5p was detected after 1h and 48h of treatment. C643 cells showed stable or up-regulated hsa-let-7f-5p, hsa-miR-146b-5p and hsa-miR-146b-3p. Selumetinib treatment caused an increase of radioiodine uptake, which was significant in TPC1 cells. Conclusions: The study shows for the first time that selumetinib restores NIS by the inhibition of its related targeting miRNAs. Further studies are needed to clarify the exact mechanism activated by hsa-miR-146b-5p, hsa-miR-146b-3p and hsa-let7f-5p to stabilise NIS. Restoration of NIS could represent a milestone for the treatment of advanced RR-DTC.

scholarly journals BRAF activates and physically interacts with PAK to regulate cell motility

2014 ◽  
Vol 21 (6) ◽  
pp. 865-877 ◽  
Author(s):  
Samantha K McCarty ◽  
Motoyasu Saji ◽  
Xiaoli Zhang ◽  
Christina M Knippler ◽  
Lawrence S Kirschner ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cell Motility ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Thyroid ◽  
Thyroid Cancer Cell ◽  
Cancer Cell Motility ◽  
Thyroid Cancer Cell Lines

Increased p21-activated kinase (PAK) signaling and expression have been identified in the invasive fronts of aggressive papillary thyroid cancers (PTCs), including those withRET/PTC, BRAFV600E, and mutantRASexpression. Functionally, thyroid cancer cell motilityin vitrois dependent on group 1 PAKs, particularly PAK1. In this study, we hypothesize that BRAF, a central kinase in PTC tumorigenesis and invasion, regulates thyroid cancer cell motility in part through PAK activation. Using three well-characterized human thyroid cancer cell lines, we demonstrated in all cell lines thatBRAFknockdown reduced PAK phosphorylation of direct downstream targets. In contrast, inhibition of MEK activity either pharmacologically or with siRNA did not reduce PAK activity, indicating MEK is dispensable for PAK activity. Inhibition of cell migration through BRAF loss is rescued by overexpression of either constitutive active MEK1 or PAK1, demonstrating that both signaling pathways are involved in BRAF-regulated cell motility. To further characterize BRAF–PAK signaling, immunofluorescence and immunoprecipitation demonstrated that both exogenously overexpressed and endogenous PAK1 and BRAF co-localize and physically interact, and that this interaction was enhanced in mitosis. Finally, we demonstrated that acute induction of BRAFV600E expressionin vivoin murine thyroid glands results in increased PAK expression and activity confirming a positive signaling relationshipin vivo. In conclusion, we have identified a signaling pathway in thyroid cancer cells which BRAF activates and physically interacts with PAK and regulates cell motility.

scholarly journals Antitumor activity of Koningic acid in thyroid cancer by inhibiting cellular glycolysis

Endocrine ◽  
2021 ◽  
Author(s):  
Changxin Jing ◽  
Yanyan Li ◽  
Zhifei Gao ◽  
Rong Wang
Keyword(s):  
Thyroid Cancer ◽  
Lactic Acid ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Colony Formation ◽  
Erk Pathway ◽  
Thyroid Cancer Cell ◽  
Thyroid Cancer Cell Lines ◽  
Thyroid Cancer Cells

Abstract Purpose Koningic acid (KA), a sesquiterpene lactone, has been identified as an antimicrobial agent. Recent studies have revealed KA’s antitumor activities in colorectal cancer, leukemia, and lung cancer. However, its antitumor effect in thyroid cancer remains largely unknown. Methods The effects of KA on proliferation, colony formation, apoptosis in thyroid cancer cells were assessed by MTT assay and flow cytometry. After KA treatment, the glycolysis ability of thyroid cancer cells was detected by ECAR, and the glycolytic products and relative ATP levels were measured by ELISA. The underlying mechanisms of antineoplastic activity of KA in thyroid cancer were detected by Western blot. Finally, the antineoplastic activity in vivo was observed in Xenograft mouse models. Results KA inhibited the proliferation, colony formation, and increased cell apoptosis in thyroid cancer cell lines in a dose and time-dependent manner. We verified that the glycolysis ability, ATP production, and lactic acid level in thyroid cancer cells had experienced an extensive decrease after KA treatment. In addition, lactic acid, the metabolite of glycolysis, could weaken the effect of KA on its colony formation ability in C643 thyroid cancer cell line. Our data also showed that KA kills thyroid cancer cells by inhibiting the MAPK/ERK pathway and decreasing Bcl-2 level. By contrast with the control group, the growth of xenograft tumor was dramatically inhibited by KA without obvious drug side effects. Conclusion Our data demonstrate that KA kills thyroid cancer cell lines by inhibiting their glycolysis ability, the MAPK/ERK pathway and the Bcl-2 level and suggest that KA has potential clinical value in thyroid cancer therapy.

scholarly journals Study On the Antitumor Bioactivity of Koningic Acid in Thyroid Cancer in Vivo and in Vitro

2021 ◽  
Author(s):  
Changxin Jing ◽  
Yanyan Li ◽  
Zhifei Gao ◽  
Peng Hou ◽  
Rong Wang
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Colony Formation ◽  
Control Group ◽  
Dependent Manner ◽  
Thyroid Cancer Cell ◽  
Xenograft Tumor ◽  
Antitumor Effects ◽  
Thyroid Cancer Cells

Abstract Purpose: Koningic acid (KA), a sesquiterpene lactone, has been identified as an antimicrobial agent. Recent studies have revealed KA’s antitumor activities in colorectal cancer, leukemia, and lung cancer. However, its antitumor effect in thyroid cancer remains largely unknown. The aim of this study is to test the therapeutic potential of KA in thyroid cancer and explore the mechanisms underlying antitumor effects.Methods: We examined the effects of KA on proliferation, colony formation, apoptosis, ATP deprivation, and xenograft tumor growth in thyroid cancer cells.Results: KA inhibited thyroid cancer cell proliferation, colony formation, and induced cell apoptosis in a dose and time-dependent manner. Our data also showed that KA caused a rapid, extensive decrease of ATP levels in thyroid cancer cells. Growth of xenograft tumor derived from the thyroid cancer cell line C643 in nude mice was significantly inhibited by KA. Importantly, KA treatment did not cause significant liver and kidney damage in mice compared with the control group.Conclusion: KA may be used as an effective and safe agent for thyroid cancer treatment.

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.

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