title: Vismodegib, an antagonist of hedgehog signaling, directly alters taste molecular signaling in taste buds.
abstract: Vismodegib, a highly selective inhibitor of hedgehog (Hh) pathway, is an approved treatment for basal-cell carcinoma. Patients on treatment with vismodegib often report profound alterations in taste sensation. The cellular mechanisms underlying the alterations have not been studied. Sonic Hh (Shh) signaling is required for cell growth and differentiation. In taste buds, Shh is exclusively expressed in type IV taste cells, which are undifferentiated basal cells and the precursors of the three types of taste sensing cells. Thus, we investigated if vismodegib has an inhibitory effect on taste cell turnover because of its known effects on Hh signaling. We gavaged C57BL/6J male mice daily with either vehicle or 30 mg/kg vismodegib for 15 weeks. The gustatory behavior and immunohistochemical profile of taste cells were examined. Vismodegib-treated mice showed decreased growth rate and behavioral responsivity to sweet and bitter stimuli, compared to vehicle-treated mice. We found that vismodegib-treated mice had significant reductions in taste bud size and numbers of taste cells per taste bud. Additionally, vismodegib treatment resulted in decreased numbers of Ki67- and Shh-expressing cells in taste buds. The numbers of phospholipase Cβ2- and α-gustducin-expressing cells, which contain biochemical machinery for sweet and bitter sensing, were reduced in vismodegib-treated mice. Furthermore, vismodegib treatment resulted in reduction in numbers of T1R3, glucagon-like peptide-1, and glucagon-expressing cells, which are known to modulate sweet taste sensitivity. These results suggest that inhibition of Shh signaling by vismodegib treatment directly results in alteration of taste due to local effects in taste buds.
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.
authors.forename: Hyekyung
authors.initials: H
authors.lastname: Yang
authors.forename: Wei-Na
authors.initials: WN
authors.lastname: Cong
authors.forename: Jeong Seon
authors.initials: JS
authors.lastname: Yoon
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Egan
mesh_terms: D000813:Anilides / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002452:Cell Count; D048429:Cell Size / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D008810:Mice, Inbred C57BL; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects*; D015398:Signal Transduction / Q000187:drug effects; D013649:Taste / Q000187:drug effects*; D013650:Taste Buds / Q000187:drug effects* / Q000502:physiology; D000071676:Zinc Finger Protein GLI1
chemical_list: D000813:Anilides; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; C538724:HhAntag691; D051741:Kruppel-Like Transcription Factors; D011725:Pyridines; D000071676:Zinc Finger Protein GLI1
keywords: Basal-cell carcinoma; Vismodegib; sonic hedgehog; taste buds; taste perception