Cyclooxygenase-2 Inhibitors Reverse Chemoresistance Phenotype in Medullary Thyroid Carcinoma by a Permeability Glycoprotein-Mediated Mechanism

Objective: Medullary thyroid carcinoma (MTC) is a highly chemoresistant malignant neoplasia deriving from parafollicular C cells. Chemotherapy failure has been ascribed, at least in part, to the overexpression by MTC of the multidrug resistance 1 (MDR1) gene, encoding a transmembrane glycoprotein [permeability glycoprotein (P-gp)] that antagonizes intracellular accumulation of cytotoxic agents. P-gp expression and function in a rat model have been demonstrated to depend on cyclooxygenase (COX)-2 isoform levels, which are found elevated in many human cancers. The aim of our study was to investigate the role of the COX-2 pathway in modulating chemoresistance. Design and Results: We investigated P-gp and COX-2 expression and then evaluated the sensitizing effects of COX-2 inhibitors on the cytotoxic effects of doxorubicin in the presence or in the absence of prostaglandin E2 in primary cultures and in a human MTC cell line, TT. Moreover, P-gp function has been studied. Our data show that TT cells express both MDR1 and COX-2 and that rofecoxib, a selective COX-2 inhibitor, sensitizes TT cells to the cytotoxic effects of doxorubicin, reducing P-gp expression and function. Conclusions: Our data suggest that these effects are mediated by a mechanism not involving the generation of prostaglandin E2, possibly implicating the synthesis of other COX-2 products.

Download Full-text

Combination of RET siRNA and irinotecan inhibited the growth of medullary thyroid carcinoma TT cells and xenografts via apoptosis

Cancer Science ◽

10.1111/j.1349-7006.2009.01484.x ◽

2010 ◽

Vol 101 (4) ◽

pp. 941-947 ◽

Cited By ~ 13

Author(s):

Kimiko Koga ◽

Yoshiyuki Hattori ◽

Mihoko Komori ◽

Ryota Narishima ◽

Masahiro Yamasaki ◽

...

Keyword(s):

Thyroid Carcinoma ◽

Medullary Thyroid Carcinoma ◽

Medullary Thyroid ◽

Tt Cells

Download Full-text

Involvement of G-quadruplex structures in regulation of human RET gene expression by small molecules in human medullary thyroid carcinoma TT cells

Oncogene ◽

10.1038/onc.2014.65 ◽

2014 ◽

Vol 34 (10) ◽

pp. 1292-1299 ◽

Cited By ~ 23

Author(s):

Y-J Shin ◽

V Kumarasamy ◽

D Camacho ◽

D Sun

Keyword(s):

Gene Expression ◽

Thyroid Carcinoma ◽

Small Molecules ◽

Medullary Thyroid Carcinoma ◽

Medullary Thyroid ◽

Ret Gene ◽

G Quadruplex ◽

Tt Cells

Download Full-text

Expression and role of estrogen receptor α and β in medullary thyroid carcinoma: different roles in cancer growth and apoptosis

Journal of Endocrinology ◽

10.1677/joe-06-0193 ◽

2007 ◽

Vol 195 (2) ◽

pp. 255-263 ◽

Cited By ~ 26

Author(s):

Mi Ae Cho ◽

Mi Kyung Lee ◽

Kee-Hyun Nam ◽

Woung Youn Chung ◽

Cheong Soo Park ◽

...

Keyword(s):

Estrogen Receptor ◽

Thyroid Carcinoma ◽

Medullary Thyroid Carcinoma ◽

Tumor Staging ◽

Estrogen Receptor Α ◽

C Cells ◽

Tissue Samples ◽

Medullary Thyroid ◽

Tt Cells

Medullary thyroid carcinoma (MTC) originates from parafollicular C cells. Estrogen receptor β(ERβ) expressionwas detected in normal parafollicular C cells and MTC tumor tissue, but ERα expression in MTC tumors still remains undetermined. The appearance and loss of ERα or ERβ expression has been known to play a role in the development and progression of many human cancers. We performed immunohistochemical studies of ERα, ERβ, and Ki67, a mitotic index, in 11 human MTC tissue samples. ERα was detected in 10 cases (91%), and ERβ expression was observed in 8 cases (72.7%). A majority (8/10) of ERα-positive tumors showing ERβ Ki67 expression was detected in three cases (27.3%). Neither clinical parameters nor tumor node metastasis (TNM) tumor staging was correlated with the positivity for ERs or Ki67. To investigate the biological role of each ER, we used ER-negative MTC TT cells and adenoviral vectors carrying ERα (Ad-ERα), ERβ (Ad-ERβ), estrogen response element (ERE)-Luc (Ad-ERE-Luc), and activator protein 1 (AP1)-Luc (Ad-AP1-Luc). Estrogen stimulated and anti-estrogen, ICI 182 780, suppressed ERE reporter activity in TT cells expressing ERα or ERβ, suggesting that both ERs use the same classical ERE-mediated pathway. Ad-ERα infection stimulated TT cell growth; in contrast, Ad-ERβ infection suppressed their growth. Apoptosis was detected in Ad-ERβ-infected TT cells. Estrogen and anti-estrogen suppressed AP1 activity in Ad-ERα-infected cells, whereas upon Ad-ERβ infection estrogen further stimulated AP1 activity which in turn is suppressed by anti-estrogen, suggesting that each ER acts differently through a non-ERE-mediated pathway. Our results suggest that ERα and ERβ may play different roles in MTC tumor growth and progression.

Download Full-text

Indomethacin Inhibits Cell Growth of Medullary Thyroid Carcinoma by Reducing Cell Cycle Progression into S Phase

Experimental Biology and Medicine ◽

10.3181/0804-rm-127 ◽

2008 ◽

Vol 233 (11) ◽

pp. 1433-1440 ◽

Cited By ~ 7

Author(s):

Chisato Tomoda ◽

Farhad Moatamed ◽

Faramarz Naeim ◽

Jerome M. Hershman ◽

Masahiro Sugawara

Keyword(s):

Cell Cycle ◽

Cell Growth ◽

Thyroid Carcinoma ◽

Medullary Thyroid Carcinoma ◽

Cell Lines ◽

Cell Cycle Progression ◽

S Phase ◽

Cycle Progression ◽

Medullary Thyroid ◽

Tt Cells

Indomethacin, a non-steroidal anti-inflammatory drug (NSAID), has been reported to inhibit the growth of medullary thyroid carcinoma (MTC) cells in vitro. However, the mechanism of inhibition of MTC cell growth by indomethacin and its potency have yet to be revealed. We examined the effect of indomethacin on three different MTC cell lines (TT cells, DRO 81–1 cells and HRO 85–1 cells) and two non-MTC cells. The mechanism of indomethacin action in MTC cells was investigated by analyzing intracellular prostaglandin level, apoptosis, and cell cycle in TT cells. Indomethacin inhibited cell growth of all three MTC cell lines but not normal thyroid cells or anaplastic thyroid carcinoma cells. Indomethacin at 10 μM or greater showed a dose response inhibition of cell growth. Indomethacin at 25 μM, a putative therapeutic serum indomethacin level, showed potency similar to 100 to 200 nM sunitinib, a receptor tyrosine kinase inhibitor. To examine whether prostaglandin depletion might determine the inhibition of MTC cell growth, we created different prostaglandin E2 (PGE2) levels in TT cells using three different NSAIDs. A profound PGE2 depletion by indomethacin-ester, a potent cyclooxygenase (COX) II inhibitor, showed the least inhibition of cell growth. Indomethacin did not increase apoptosis of TT cells. Indomethacin, but not naproxen or indomethacin-ester, reduced cell cycle progression into S phase; this was unrelated to the degree of PGE2 depletion. The expression of phosphorylated retinoblastoma (pRb) protein that shifts cells from G1 to S phase was reduced after exposure to indomethacin. In conclusion, indomethacin has specific anti-tumor effect on MTC cells, probably by reducing cell cycle progression into S phase rather than by prostaglandin depletion. Since no drug therapy is currently available for MTC, indomethacin may be one of the therapeutic candidates.

Download Full-text

Selective Antitumor Activity of Datelliptium toward Medullary Thyroid Carcinoma by Downregulating RET Transcriptional Activity

Cancers ◽

10.3390/cancers13133288 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3288

Author(s):

Tariq Alqahtani ◽

Abdullah Alswied ◽

Daekyu Sun

Keyword(s):

Antitumor Activity ◽

Thyroid Carcinoma ◽

Medullary Thyroid Carcinoma ◽

Time Course ◽

Epithelial To Mesenchymal Transition ◽

Dependent Manner ◽

Mesenchymal Transition ◽

Medullary Thyroid ◽

Transcription Inhibitor ◽

Tt Cells

Medullary thyroid carcinoma (MTC) is a rare aggressive form of thyroid cancer with high rates of metastasis. Sporadic and hereditary MTC are strongly driven by somatic and germline mutations, respectively, in the transmembrane REarranged during Transfection (RET) proto-oncogene, which encodes a receptor tyrosine kinase. Our previous study identified datelliptium as a novel RET transcription inhibitor, which stabilizes the RET G-quadruplex structures and suppresses RET oncogene transcription. The present study aimed to elucidate the effect of datelliptium on the suppression of epithelial-to-mesenchymal transition (EMT) and metastasis-related behaviors of MTC cells, including cell migration and formation of cancer stem cells (CSCs). Our results demonstrated that datelliptium downregulated the expression of the mesenchymal markers, including N-cadherin, vimentin, slug, snail, and claudin-1. Compared to untreated cells, datelliptium significantly decreased the migration of TT cells in a dose-dependent manner in a wound healing assay. Additionally, datelliptium significantly reduced the size of preformed spheroids from TT cells over the time course. Finally, datelliptium inhibited approximately 75% of MTC xenograft growth with minimal systemic toxicity. In conclusion, datelliptium exerts its antitumor activity against MTC cells by reducing the EMT program, migratory ability, and self-renewal capacity of TT cells, thus preventing invasive and metastatic behavior of MTC.

Download Full-text

Role of Pituitary Tumour Transforming Gene 1 in Medullary Thyroid Carcinoma

Analytical Cellular Pathology ◽

10.1155/2010/472067 ◽

2010 ◽

Vol 33 (5-6) ◽

pp. 207-216 ◽

Cited By ~ 6

Author(s):

Maria Chiara Zatelli ◽

Federico Tagliati ◽

Vincenzo Amodio ◽

Mattia Buratto ◽

Mariarosa Pelizzo ◽

...

Keyword(s):

Thyroid Carcinoma ◽

Dna Synthesis ◽

Medullary Thyroid Carcinoma ◽

Pituitary Tumour ◽

Cell Hyperplasia ◽

Medullary Thyroid ◽

C Cell Hyperplasia ◽

C Cell ◽

Tt Cells ◽

Transforming Gene

Background: Pituitary tumour transforming gene 1 (PTTG1) is over-expressed in a variety of endocrine-related tumours. We aimed at evaluatingPTTG1expression and function in human neoplastic parafollicular C-cells, represented by medullary thyroid carcinoma (MTC) and C-cell hyperplasia (CCH) samples and by the TT cell line.Methods: TT cells and tissues derived from human CCH (8 samples) and MTC (12 samples) were analyzed by northern blot, furthermore TT cells were subjected to PTTG gene silencing and cells were analyzed for DNA synthesis.Results:PTTG1expression was significantly higher (p< 0.01) in CCH (3-fold), in papillary thyroid cancer and in MTC (5-fold) than in normal thyroid, and in MTC lymph-node metastases as compared to primary lesions (~2-fold; p < 0.05).PTTG1mRNA and protein correlated with tumour diameter and TNM status (p < 0.05). In TT cells,PTTG1silencing did not completely block DNA synthesis, but significantly reduced [3H]Thymidine incorporation (~50%; p < 0.01) for up to 3 days.Conclusion:PTTG1levels correlate with tumour aggressiveness.PTTG1silencing causes reduced MTC cell proliferation, supporting the hypothesis thatPTTG1might have an important role in C-cell neoplastic proliferation.

Download Full-text

Protein Kinase C: A Putative New Target for the Control of Human Medullary Thyroid Carcinoma Cell Proliferation in Vitro

Endocrinology ◽

10.1210/en.2011-1988 ◽

2012 ◽

Vol 153 (5) ◽

pp. 2088-2098 ◽

Cited By ~ 12

Author(s):

Daniela Molè ◽

Erica Gentilin ◽

Teresa Gagliano ◽

Federico Tagliati ◽

Marta Bondanelli ◽

...

Keyword(s):

Cell Proliferation ◽

Protein Kinase C ◽

Protein Kinase ◽

Thyroid Carcinoma ◽

Medullary Thyroid Carcinoma ◽

Glycogen Synthase ◽

Primary Cultures ◽

Medullary Thyroid ◽

Kinase C

We investigate the role of protein kinase C (PKC) in the control of medullary thyroid carcinoma (MTC) cell proliferation by a PKC inhibitor, Enzastaurin, in human MTC primary cultures and in the TT cell line. We found that PKC inhibition reduces cell proliferation by inducing caspase-mediated apoptosis and blocks the stimulatory effect of IGF-I on calcitonin secretion. Enzastaurin reduces PKCβII (Thr500) phosphorylation, indicating a direct involvement of this isoform as well as the phosphorylated levels of Akt (Ser 473) and glycogen synthase kinase (Ser9), PKC pathway downstream targets and pharmacodynamic markers for PKC inhibition. PKCβII and PKCδ enzyme isoforms expression and localization were investigated. These data indicate that in vitro PKC is involved in the control of human MTC proliferation and survival by modulating apoptosis, with a mechanism that implicates PKCβII inhibition and translocation in different subcellular compartments. Targeting PKC may represent a useful therapeutic approach for controlling MTC proliferation.

Download Full-text