title: Thiocoraline alters neuroendocrine phenotype and activates the Notch pathway in MTC-TT cell line.
abstract: Medullary thyroid cancer (MTC) is an aggressive neuroendocrine tumor (NET). Previous research has shown that activation of Notch signaling has a tumor suppressor role in NETs. The potential therapeutic effect of thiocoraline on the activation of the Notch pathway in an MTC cell line (TT) was investigated. Thiocoraline was isolated from a marine bacterium Verrucosispora sp. MTT assay (3-[4, 5-dimethylthiazole-2-yl]-2, 5-diphenyltetrazolium bromide) was used to determine the IC50 value and to measure cell proliferation. Western blot revealed the expression of Notch isoforms, NET, and cell cycle markers. Cell cycle progression was validated by flow cytometry. The mRNA expression of Notch isoforms and downstream targets were measured using real-time PCR. The IC50 value for thiocoraline treatment in TT cells was determined to be 7.6 nmol/L. Thiocoraline treatment decreased cell proliferation in a dose- and time-dependent manner. The mechanism of growth inhibition was found to be cell cycle arrest in G1 phase. Thiocoraline activated the Notch pathway as demonstrated by the dose-dependent increase in mRNA and protein expression of Notch isoforms. Furthermore, treatment with thiocoraline resulted in changes in the expression of downstream targets of the Notch pathway (HES1, HES2, HES6, HEY1, and HEY2) and reduced expression of NET markers, CgA, and ASCL1. Thiocoraline is a potent Notch pathway activator and an inhibitor of MTC-TT cell proliferation at low nanomolar concentrations. These results provide exciting evidence for the use of thiocoraline as a potential treatment for intractable MTC.
authors.affiliation: University of Wisconsin Medical School, Madison, Wisconsin.
authors.forename: Sara
authors.initials: S
authors.lastname: Tesfazghi
authors.forename: Jacob
authors.initials: J
authors.lastname: Eide
authors.forename: Ajitha
authors.initials: A
authors.lastname: Dammalapati
authors.forename: Colin
authors.initials: C
authors.lastname: Korlesky
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Wyche
authors.forename: Tim S
authors.initials: TS
authors.lastname: Bugni
authors.forename: Herbert
authors.initials: H
authors.lastname: Chen
authors.forename: Renata
authors.initials: R
authors.lastname: Jaskula-Sztul
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018278:Carcinoma, Neuroendocrine / Q000378:metabolism / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D047630:Depsipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010641:Phenotype; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D051880:Receptors, Notch; C109005:thiocoraline
keywords: Cell cycle; Notch signaling; medullary thyroid cancer; neuroendocrine cancer; thiocoraline