title: Tumor-suppressor role of Notch3 in medullary thyroid carcinoma revealed by genetic and pharmacological induction.
abstract: Notch1-3 are transmembrane receptors that appear to be absent in medullary thyroid cancer (MTC). Previous research has shown that induction of Notch1 has a tumor-suppressor effect in MTC cell lines, but little is known about the biologic consequences of Notch3 activation for the progression of the disease. We elucidate the role of Notch3 in MTC by genetic (doxycycline-inducible Notch3 intracellular domain) and pharmacologic [AB3, novel histone deacetylase (HDAC) inhibitor] approaches. We find that overexpression of Notch3 leads to the dose-dependent reduction of neuroendocrine tumor markers. In addition, Notch3 activity is required to suppress MTC cell proliferation, and the extent of growth repression depends on the amount of Notch3 protein expressed. Moreover, activation of Notch3 induces apoptosis. The translational significance of this finding is highlighted by our observation that MTC tumors lack active Notch3 protein and reinstitution of this isoform could be a therapeutic strategy to treat patients with MTC. We demonstrate, for the first time, that overexpression of Notch3 in MTC cells can alter malignant neuroendocrine phenotype in both in vitro and in vivo models. In addition, our study provides a strong rationale for using Notch3 as a therapeutic target to provide novel pharmacologic treatment options for MTC.
authors.affiliation: Department of Surgery, University of Wisconsin Medical School, Madison, Wisconsin.
authors.forename: Renata
authors.initials: R
authors.lastname: Jaskula-Sztul
authors.affiliation: Department of Surgery, University of Wisconsin Medical School, Madison, Wisconsin.
authors.forename: Jacob
authors.initials: J
authors.lastname: Eide
authors.affiliation: Department of Surgery, University of Wisconsin Medical School, Madison, Wisconsin.
authors.forename: Sara
authors.initials: S
authors.lastname: Tesfazghi
authors.affiliation: Department of Surgery, University of Wisconsin Medical School, Madison, Wisconsin.
authors.forename: Ajitha
authors.initials: A
authors.lastname: Dammalapati
authors.affiliation: Department of Surgery, University of Wisconsin Medical School, Madison, Wisconsin.
authors.forename: April D
authors.initials: AD
authors.lastname: Harrison
authors.affiliation: Department of Surgery, University of Wisconsin Medical School, Madison, Wisconsin.
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Yu
authors.affiliation: School of Pharmacy and Department of Chemistry, University of Wisconsin, Madison, Wisconsin.
authors.forename: Casi
authors.initials: C
authors.lastname: Scheinebeck
authors.affiliation: School of Pharmacy and Department of Chemistry, University of Wisconsin, Madison, Wisconsin.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Winston-McPherson
authors.affiliation: Promega Corporation, Madison, Wisconsin.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Kupcho
authors.affiliation: Promega Corporation, Madison, Wisconsin.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Robers
authors.affiliation: Department of Surgery, University of Wisconsin Medical School, Madison, Wisconsin.
authors.forename: Amrit K
authors.initials: AK
authors.lastname: Hundal
authors.affiliation: School of Pharmacy and Department of Chemistry, University of Wisconsin, Madison, Wisconsin. chen@surgery.wisc.edu wtang@pharmacy.wisc.edu.
authors.forename: Weiping
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Surgery, University of Wisconsin Medical School, Madison, Wisconsin. chen@surgery.wisc.edu wtang@pharmacy.wisc.edu.
authors.forename: Herbert
authors.initials: H
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018278:Carcinoma, Neuroendocrine; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008819:Mice, Nude; D009490:Neurosecretory Systems / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D054852:Small Molecule Libraries; D025521:Tumor Suppressor Proteins