hes1-protein--human and Thyroid-Carcinoma--Anaplastic

Anaplastic thyroid cancer (ATC) is characterized by very aggressive growth with undifferentiated features. Recently, it has been reported that the Notch1 signaling pathway, which affects thyrocyte proliferation and differentiation, is inactivated in ATC. However, it remains largely unknown whether using Notch1 activating compounds can be an effective therapeutic strategy in ATC. Therefore, in this study, we aimed to evaluate the drug effects of a potential Notch activator hesperetin on ATC cell.. A unique ATC cell line HTh7 was used to evaluate the drug effects of hesperetin. The Notch1 activating function and cell proliferation were evaluated. The mechanism of growth regulation was investigated by the detection of apoptotic markers. The expression levels of thyrocyte-specific genes were quantified for ATC redifferentiation.. Upregulated expression of Notch1 and its downstream effectors hairy and enhancer of split 1 (Hes1) and Hes1 related with YRPW motif was observed in hesperetin-treated ATC cells. The enhanced luciferase signal also confirmed the functional activity of hesperetin-induced Notch1 signaling. Hesperetin led to a time- and dose-dependent decrease in ATC cell proliferation. The cell-growth inhibition was mainly caused by apoptosis as evidenced by increased levels of cleaved poly ADP ribose polymerase and cleaved caspase-3 as well as decreased survivin. Additionally, hesperetin induced the expression levels of thyrocyte-specific genes including thyroid transcription factor 1 (TTF1), TTF2, paired box gene 8, thyroid stimulating hormone receptor, and sodium/iodide symporter.. Hesperetin activates the Notch1 signaling cascade and suppresses ATC cell proliferation mainly via apoptosis. Hesperetin also induces cell redifferentiation of ATC, which could be useful clinically.

Topics: Adenosine Triphosphatases; Antineoplastic Agents; Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Cell Cycle Proteins; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; DNA-Binding Proteins; Gene Expression; Hesperidin; Homeodomain Proteins; Humans; Nuclear Proteins; Paired Box Transcription Factors; PAX8 Transcription Factor; Receptor, Notch1; Receptors, Thyrotropin; Signal Transduction; Symporters; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Thyroid Nuclear Factor 1; Transcription Factor HES-1; Transcription Factors

Anaplastic thyroid cancer (ATC) is a very aggressive thyroid gland malignancy with very poor prognosis. It is suspected that the Notch signaling pathway, which is not active in ATC, may have a tumor suppressor function in this neoplasm. However, it remains unknown whether activation of Notch can yield therapeutic efficacies in ATC.. The purpose of this study was to evaluate the effect of chrysin, a potential Notch inducer identified via high-throughput screening, on ATC both in vitro and in vivo.. Chrysin treatment of ATC cells led to a dose-dependent inhibition of cellular growth. Protein and messenger RNA levels of Notch1 and Hes1 (hairy/enhancer of split 1), a downstream Notch1 effector, were both up-regulated with treatment. Luciferase reporter assays incorporating the C promoter-binding factor 1 (CBF1) binding site also confirmed the functional activity of chrysin-induced Notch1. Oral administration of chrysin suppressed the growth of ATC xenografts by an average of 59% compared with the vehicle control group (P = .002). In addition, calculated median time to tumor progression was 11 days for control mice and 21 days for the chrysin treatment group (P = .008). Analysis of chrysin-treated ATC tumors revealed an increase in the active intracellular domain of Notch1 protein. Activation of Notch1 in vivo was associated with the induction of cleaved Poly ADP ribose polymerase (PARP) protein, indicating that the growth inhibition was due to apoptosis.. The novel Notch1 activator chrysin inhibits tumor growth in ATC both in vitro and in vivo. Chrysin could be a promising therapeutic candidate for ATC, and this justifies further clinical studies.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Basic Helix-Loop-Helix Transcription Factors; Cell Line, Tumor; Cell Proliferation; Flavonoids; Gene Expression Regulation, Neoplastic; Homeodomain Proteins; Humans; Male; Mice; Mice, Nude; Poly(ADP-ribose) Polymerases; Receptor, Notch1; Signal Transduction; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Transcription Factor HES-1; Xenograft Model Antitumor Assays