Galectin-3 Inhibitors Suppress Anoikis Resistance and Invasive Capacity in Thyroid Cancer Cells

Accumulating evidence suggests that galectin-3 is a histologic marker of thyroid cancer. However, the pharmacological lectin-based approach has not been well studied. In the present study, we aimed to investigate the therapeutic potential of novel galectin-3 inhibitors by treating thyroid cancer cells with different concentrations of GB1107 or TD139. At high doses, TD139, but not GB1107, reduced cell viability and clonogenicity of thyroid cancer cells. TD139 induced apoptosis of thyroid cancer cells, as evident by an increase in the percentage of sub-G1 cells on cell cycle analysis, caspase-3 activation, and PARP1 cleavage. Either GB1107 or TD139 significantly inhibited cell coherence and counteracted anoikis resistance. Both inhibitors decreased migratory and invasive abilities in a dose-dependent manner. Furthermore, GB1107 and TD139 treatment attenuated AKT phosphorylation and decreased the expression of β-catenin and MMP2. In conclusion, these novel galectin-3 inhibitors suppressed the anoikis resistance, motility, and invasive capacity of thyroid cancer cells at least partly through the AKT/β-catenin pathway. Galectin-3 inhibitors are potentially suitable for preclinical evaluation of treatment and/or prevention of metastatic spread in thyroid cancer.

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Quercetin Induces Anticancer Activity by Upregulating Pro-NAG-1/GDF15 in Differentiated Thyroid Cancer Cells

Cancers ◽

10.3390/cancers13123022 ◽

2021 ◽

Vol 13 (12) ◽

pp. 3022

Author(s):

Yukyung Hong ◽

Jaehak Lee ◽

Hyunjin Moon ◽

Chang H. Ryu ◽

Jungirl Seok ◽

...

Keyword(s):

Thyroid Cancer ◽

Anticancer Activity ◽

Cancer Cells ◽

Cancer Prognosis ◽

Antibody Array ◽

Dependent Manner ◽

Normal Tissues ◽

Cycle Arrest ◽

Novel Biomarkers ◽

Thyroid Cancer Cells

Although the treatment of thyroid cancer has improved, unnecessary surgeries are performed due to a lack of specific diagnostic and prognostic markers. Therefore, the identification of novel biomarkers should be considered in the diagnosis and treatment of thyroid cancer. In this study, antibody arrays were performed using tumor and adjacent normal tissues of patients with papillary thyroid cancer, and several potential biomarkers were identified. Among the candidate proteins chosen based on the antibody array data, mature NAG-1 exhibited increased expression in tumor tissues compared to adjacent normal tissues. In contrast, pro-NAG-1 expression increased in normal tissues, as assessed by western blot analysis. Furthermore, pro-NAG-1 expression was increased when the thyroid cancer cells were treated with phytochemicals and nonsteroidal anti-inflammatory drugs in a dose-dependent manner. In particular, quercetin highly induced the expression of pro-NAG-1 but not that of mature NAG-1, with enhanced anticancer activity, including apoptosis induction and cell cycle arrest. Examination of the NAG-1 promoter activity showed that p53, C/EBPα, or C/EBPδ played a role in quercetin-induced NAG-1 expression. Overall, our study indicated that NAG-1 may serve as a novel biomarker for thyroid cancer prognosis and may be used as a therapeutic target for thyroid cancers.

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Galectin-3 regulates apoptosis and doxorubicin chemoresistance in papillary thyroid cancer cells

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2008.12.153 ◽

2009 ◽

Vol 379 (2) ◽

pp. 626-631 ◽

Cited By ~ 40

Author(s):

Chi-Iou Lin ◽

Edward E. Whang ◽

Michael A. Abramson ◽

David B. Donner ◽

Monica M. Bertagnolli ◽

...

Keyword(s):

Thyroid Cancer ◽

Cancer Cells ◽

Papillary Thyroid Cancer ◽

Papillary Thyroid ◽

Galectin 3 ◽

Thyroid Cancer Cells

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

Journal of Endocrinology ◽

10.1677/joe.0.1690417 ◽

2001 ◽

Vol 169 (2) ◽

pp. 417-424 ◽

Cited By ~ 24

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.

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The Akt-Specific Inhibitor MK2206 Selectively Inhibits Thyroid Cancer Cells Harboring Mutations That Can Activate the PI3K/Akt Pathway

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2010-2644 ◽

2011 ◽

Vol 96 (4) ◽

pp. E577-E585 ◽

Cited By ~ 65

Author(s):

Ruixin Liu ◽

Dingxie Liu ◽

Eliana Trink ◽

Ermal Bojdani ◽

Guang Ning ◽

...

Keyword(s):

Thyroid Cancer ◽

Cancer Cells ◽

Therapeutic Potential ◽

Mammalian Target Of Rapamycin ◽

Specific Inhibitor ◽

Akt Pathway ◽

Akt Inhibitor ◽

Cancer Cell Growth ◽

Ic50 Values ◽

Thyroid Cancer Cells

Abstract Context: The phosphoinositide 3-kinase (PI3K)/Akt pathway is widely postulated to be an effective therapeutic target in thyroid cancer. Objective: The aim of the study was to test the therapeutic potential of the novel Akt inhibitor MK2206 for thyroid cancer. Design: We examined the effects of MK2206 on thyroid cancer cells with respect to the genotypes of the PI3K/Akt pathway. Results: Proliferation of thyroid cancer cells OCUT1, K1, FTC133, C643, Hth7, and TPC1, which harbored PIK3CA, PTEN, Ras, or RET/PTC mutations that could activate the PI3K/Akt pathway, was potently inhibited by MK2206 with IC50 values mostly below or around 0.5 μm. In contrast, no potent inhibition by MK2206 was seen in most of the Hth74, KAT18, SW1736, WRO, and TAD2 cells that did not harbor mutations in the PI3K/Akt pathway. The inhibition efficacy was also genetic-selective. Specifically, the average inhibition efficacies were 59.2 ± 11.3 vs. 36.4 ± 8.8% (P = 0.005) at 1 μm MK2206 and 64.4 ± 11.5 vs. 38.5 ± 18.9% (P = 0.02) at 3 μm MK2206 for cells with mutations vs. cells without. The SW1736 cell, lacking mutations in the PI3K/Akt pathway, had minimal response to MK2206, but transfection with exogenous PIK3CA mutants, PIK3CA H1047R and E545K, significantly increased its sensitivity to MK2206. MK2206 also completely overcame the feedback activation of Akt from temsirolimus-induced mammalian target of rapamycin suppression, and the two inhibitors synergistically inhibited thyroid cancer cell growth. Conclusions: Our study demonstrates a genetic selectivity of MK2206 in inhibiting thyroid cancer cells by targeting the PI3K/Akt pathway, supporting a clinical trial in thyroid cancer.

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Induction of Thyroid Gene Expression and Radioiodine Uptake in Thyroid Cancer Cells by Targeting Major Signaling Pathways

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-1888 ◽

2010 ◽

Vol 95 (2) ◽

pp. 820-828 ◽

Cited By ~ 62

Author(s):

Peng Hou ◽

Ermal Bojdani ◽

Mingzhao Xing

Keyword(s):

Gene Expression ◽

Thyroid Cancer ◽

Cancer Cells ◽

Signaling Pathways ◽

Histone Deacetylase ◽

Sodium Iodide ◽

Therapeutic Potential ◽

Sodium Iodide Symporter ◽

Thyroid Cells ◽

Thyroid Cancer Cells

Abstract Context: Radioiodine ablation is commonly used to treat thyroid cancer, but a major challenge is often the loss of radioiodine avidity of the cancer caused by aberrant silencing of iodide-handling genes. Objectives: This study was conducted to test the therapeutic potential of targeting the aberrantly activated MAPK and PI3K/Akt/mTOR pathways and histone deacetylase to restore radioiodine avidity in thyroid cancer cells. Experimental Design: We tested the effects of specific inhibitors targeting these pathways/molecules that had established clinical applicability, including the MAPK kinase inhibitor RDEA119, mTOR inhibitor temsirolimus, Akt inhibitor perifosine, and histone deacetylase inhibitor SAHA, individually or in combinations, on the expression of iodide-handling genes and radioiodide uptake in a large panel of thyroid cancer cell lines. Results: The expression of a large number of iodide-handling genes could be restored, particularly the sodium/iodide symporter, TSH receptor, and thyroperoxidase, by treating cells with these inhibitors. The effect was particularly robust and synergistic when combinations of inhibitors containing SAHA were used. Robust expression of sodium/iodide symporter in the cell membrane, which plays the most important role in iodide uptake in thyroid cells, was confirmed by immunofluorescent microscopy. Radioiodide uptake by cells was correspondingly induced under these conditions. Thyroid gene expression and radioiodide uptake could both be further enhanced by TSH. Conclusions: Targeting major signaling pathways could restore thyroid gene expression and radioiodide uptake in thyroid cancer cells. Further studies are warranted to test this therapeutic potential in restoring radioiodine avidity of thyroid cancer cells for effective ablation treatment.

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

10.21203/rs.3.rs-449260/v1 ◽

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.

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Long Non-Coding RNA MAPK8IP1P2 Inhibits Lymphatic Metastasis of Thyroid Cancer by Activating Hippo Signaling via Sponging miR-146b-3p

Frontiers in Oncology ◽

10.3389/fonc.2020.600927 ◽

2021 ◽

Vol 10 ◽

Author(s):

Xiaoli Liu ◽

Qingfeng Fu ◽

Xuehai Bian ◽

Yantao Fu ◽

Jingwei Xin ◽

...

Keyword(s):

Thyroid Cancer ◽

Cancer Cells ◽

Lymphatic Metastasis ◽

Inhibitory Effect ◽

Hippo Signaling ◽

Anoikis Resistance ◽

Potential Biomarker ◽

Thyroid Cancer Cells

The principal issue derived from thyroid cancer is its high propensity to metastasize to the lymph node. Aberrant exprssion of long non-coding RNAs have been extensively reported to be significantly correlated with lymphatic metastasis of thyroid cancer. However, the clinical significance and functional role of lncRNA-MAPK8IP1P2 in lymphatic metastasis of thyroid cancer remain unclear. Here, we reported that MAPK8IP1P2 was downregulated in thyroid cancer tissues with lymphatic metastasis. Upregulating MAPK8IP1P2 inhibited, while silencing MAPK8IP1P2 enhanced anoikis resistance in vitro and lymphatic metastasis of thyroid cancer cells in vivo. Mechanistically, MAPK8IP1P2 activated Hippo signaling by sponging miR-146b-3p to disrupt the inhibitory effect of miR-146b-3p on NF2, RASSF1, and RASSF5 expression, which further inhibited anoikis resistance and lymphatic metastasis in thyroid cancer. Importantly, miR-146b-3p mimics reversed the inhibitory effect of MAPK8IP1P2 overexpression on anoikis resistance of thyroid cancer cells. In conclusion, our findings suggest that MAPK8IP1P2 may serve as a potential biomarker to predict lymphatic metastasis in thyroid cancer, or a potential therapeutic target in lymphatic metastatic thyroid cancer.

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

10.1101/2019.12.20.885483 ◽

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.

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High Iodine Induces the Proliferation of Papillary and Anaplastic Thyroid Cancer Cells via AKT/Wee1/CDK1 Axis

Frontiers in Oncology ◽

10.3389/fonc.2021.622085 ◽

2021 ◽

Vol 11 ◽

Author(s):

Chunpeng Lv ◽

Yanhui Gao ◽

Jinyin Yao ◽

Yan Li ◽

Qun Lou ◽

...

Keyword(s):

Cell Cycle ◽

Thyroid Cancer ◽

Cancer Cells ◽

Cell Cycle Progression ◽

Anaplastic Thyroid Cancer ◽

Underlying Mechanism ◽

High Iodine ◽

Akt Phosphorylation ◽

Thyroid Cancer Cells

High iodine can alter the proliferative activity of thyroid cancer cells, but the underlying mechanism has not been fully elucidated. Here, the role of high iodine in the proliferation of thyroid cancer cells was studied. In this study, we demonstrated that high iodine induced the proliferation of BCPAP and 8305C cells via accelerating cell cycle progression. The transcriptome analysis showed that there were 295 differentially expressed genes (DEGs) in BCPAP and 8305C cells induced by high iodine, among which CDK1 expression associated with the proliferation of thyroid cancer cells induced by high iodine. Moreover, the western blot analysis revealed that cells exposed to high iodine enhanced the phosphorylation activation of AKT and the expression of phospho-Wee1 (Ser642), while decreasing the expression of phospho-CDK1 (Tyr15). Importantly, the inhibition of AKT phosphorylation revered the expression of CDK1 induced by high iodine and arrested the cell cycle in the G1 phase, decreasing the proliferation of thyroid cancer cells induced by high iodine. Taken together, these findings suggested that high iodine induced the proliferation of thyroid cancer cells through AKT-mediated Wee1/CDK1 axis, which provided new insights into the regulation of proliferation of thyroid cancer cells by iodine.

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