title: Hesperetin activates the Notch1 signaling cascade, causes apoptosis, and induces cellular differentiation in anaplastic thyroid cancer.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Priyesh N
authors.initials: PN
authors.lastname: Patel
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Yu
authors.forename: Renata
authors.initials: R
authors.lastname: Jaskula-Sztul
authors.forename: Herbert
authors.initials: H
authors.lastname: Chen
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006569:Hesperidin / Q000494:pharmacology*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D011989:Receptors, Thyrotropin / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D027981:Symporters / Q000235:genetics; D065646:Thyroid Carcinoma, Anaplastic / Q000188:drug therapy*; D013964:Thyroid Neoplasms / Q000188:drug therapy*; D000074482:Thyroid Nuclear Factor 1; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000235:genetics; D000099209:Sodium-Iodide Symporters
chemical_list: D000251:Adenosine Triphosphatases; D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006569:Hesperidin; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D051881:Receptor, Notch1; D011989:Receptors, Thyrotropin; D027981:Symporters; D000074482:Thyroid Nuclear Factor 1; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; D000099209:Sodium-Iodide Symporters; C485631:HEY1 protein, human; C000614412:NKX2-1 protein, human; C497761:NOTCH1 protein, human; C083325:PAX8 protein, human; C078493:HES1 protein, human; C477874:TTF2 protein, human; C013015:hesperetin