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

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.

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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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Thyroid Cancer Cell Resistance to gefitinib Depends on the Constitutive Oncogenic Activation of the ERK Pathway

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2012-3623 ◽

2013 ◽

Vol 98 (6) ◽

pp. 2502-2512 ◽

Cited By ~ 13

Author(s):

Francesco Frasca ◽

Veronica Vella ◽

Maria Luisa Nicolosi ◽

Rosa Linda Messina ◽

Fiorenza Gianì ◽

...

Keyword(s):

Thyroid Cancer ◽

Tyrosine Kinase ◽

Cell Lines ◽

Cancer Cell ◽

Braf V600e ◽

Erk Pathway ◽

Thyroid Cancer Cell ◽

Epidermal Growth ◽

Thyroid Cancer Cell Lines ◽

Thyroid Cancer Cells

Context: Poorly differentiated thyroid carcinomas are refractory to common anticancer therapies, and novel inhibitors are being tested in these deadly malignancies. The epidermal growth factor receptor (EGFR) tyrosine kinase represents an attractive target for treatment because it is up-regulated in thyroid cancer and plays a role in cancer progression. However, EGFR inhibitors have provided poor results in thyroid carcinomas. Objective: We evaluated the possible mechanism underlying the resistance of thyroid cancer cells to EGFR inhibitors. Design: We tested the effect of the EGFR tyrosine kinase inhibitor gefitinib in a panel of thyroid cancer cell lines. Results: We found that in most of the cell lines, although gefitinib inhibited EGFR phosphorylation, it was poorly effective in reducing cell viability. gefitinib, however, was able to inhibit epidermal growth factor-induced cell migration and matrix invasion. In most thyroid cancer cell lines, gefitinib significantly inhibited Akt phosphorylation by inhibiting EGFR activation, but it had limited or no effect on ERK phosphorylation. The poor cell response to gefitinib was associated with genetic alterations, leading to constitutive activation of the ERK pathway, including BRAF(V600E) and HRASG12A/Q61R mutations and RET/PTC1 rearrangement. When BRAF(V600E)-positive thyroid cancer cells were incubated with the specific BRAF inhibitor PLX4032, sensitivity to gefitinib was restored. Similar results were obtained with rat sarcoma and RET/papillary thyroid cancer inhibitors. Conclusions: These results indicate that thyroid cancer resistance to gefitinib is due to the constitutive activation of the mitogenic pathway by either signals downstream of EGFR or other tyrosine kinase receptors. This resistance can be overcome by the combined use of selective inhibitors.

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

International Journal of Molecular Sciences ◽

10.3390/ijms19072077 ◽

2018 ◽

Vol 19 (7) ◽

pp. 2077 ◽

Cited By ~ 7

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.

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Demethylation of TMS1 Gene Sensitizes Thyroid Cancer Cells to TRAIL-Induced Apoptosis

Molecular Endocrinology ◽

10.1210/mend.24.11.9998 ◽

2010 ◽

Vol 24 (11) ◽

pp. 2241-2242

Author(s):

Abdul K. Siraj ◽

Azhar R. Hussain ◽

Maha Al-Rasheed ◽

Maqbool Ahmed ◽

Prashant Bavi ◽

...

Keyword(s):

Thyroid Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Methylation Status ◽

Cancer Cell Lines ◽

Thyroid Cancer Cell ◽

Induced Apoptosis ◽

Thyroid Cancer Cell Lines ◽

Thyroid Cancer Cells

Abstract Context: TMS1 is a tumor suppressor gene that encodes for caspase recruitment domain containing regulatory protein and has been shown to be hypermethylated in various cancers. However, its methylation status has not been investigated in thyroid cancer. Therefore, we studied the methylation of TMS1 and its functional consequence in thyroid cancer. Design: The methylation status of the promoter region of the TMS1 gene was determined using methylation-specific PCR in 40 papillary thyroid cancer samples, 10 normal thyroid tissue, and seven thyroid cancer cell lines. RT-PCR and Western blot analysis were used to assess the expression levels. 5-aza-2′-deoxycytidine was used to demethylate the thyroid cancer cell lines. Cell viability and apoptosis was determined by dimethylthiazoldiphenyltetra-zoliumbromide and flow cytometry. Results: Twenty-three percent of the papillary thyroid carcinoma samples were found to be methylated for the TMS1 gene. Two of seven thyroid cell lines were either completely or partially methylated for the TMS1 gene. The treatment of methylated thyroid cancer cell lines with 5-aza-2′-deoxycytidine resulted in the demethylation of the TMS1 gene leading to the restoration of its expression. After demethylation, treatment of cells with TNF-related apoptosis-inducing ligand (TRAIL) led to the induction of apoptosis via activation of caspases-8, caspase-3, and poly(ADP-ribose) polymerase. Interestingly, gene silencing of TMS1 using TMS1-specific small interfering RNA prevented TRAIL-mediated apoptosis. Conclusion: Our results demonstrated that the TMSI gene is methylated in thyroid cancer cells and repression of methylation by 5-aza-2′-deoxycytidine restored expression of the TMS1 gene and sensitized cells to TRAIL-induced apoptosis. These findings suggest that the TMS1 gene can be targeted by combination of demethylating agents with TRAIL to induce efficient apoptosis in thyroid cancer cells.

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

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/3900330 ◽

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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