Cargando…

Solasonine, A Natural Glycoalkaloid Compound, Inhibits Gli-Mediated Transcriptional Activity

The major obstacle limiting the efficacy of current Smoothened (Smo) inhibitors is the primary and acquired resistance mainly caused by Smo mutations and Gli amplification. In this context, developing Hh inhibitors targeting Gli, the final effector of this signaling pathway, may combat the resistanc...

Descripción completa

Detalles Bibliográficos
Autores principales: Yang, Jun, Huang, Wenjing, Tan, Wenfu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274431/
https://www.ncbi.nlm.nih.gov/pubmed/27754442
http://dx.doi.org/10.3390/molecules21101364
_version_ 1783377616703586304
author Yang, Jun
Huang, Wenjing
Tan, Wenfu
author_facet Yang, Jun
Huang, Wenjing
Tan, Wenfu
author_sort Yang, Jun
collection PubMed
description The major obstacle limiting the efficacy of current Smoothened (Smo) inhibitors is the primary and acquired resistance mainly caused by Smo mutations and Gli amplification. In this context, developing Hh inhibitors targeting Gli, the final effector of this signaling pathway, may combat the resistance. In this study we found that solasonine, a natural glycoalkaloid compound, significantly inhibited the hedgehog (Hh) pathway activity. Meanwhile, solasonine may obviously inhibit the alkaline phosphatase (ALP) activity in C3H10T1/2 cells, concomitantly with reductions of the mRNA expression of Gli1 and Ptch1. However, we found that solasonine exhibited no effect on the transcriptional factors activities provoked by TNF-α and PGE2, thus suggesting its selectivity against Hh pathway activity. Furthermore, we identified that solasonine inhibited the Hh pathway activity by acting on its transcriptional factor Gli using a series of complementary data. We also observed that solasonine obviously inhibited the Gli-luciferase activity provoked by ectopic expression of Smo mutants which may cause the resistance to the current Smo inhibitors. Our study suggests that solasonine may significantly inhibit the Hh pathway activity by acting on Gli, therefore indicating the possibility to use solasonine as a lead compound to develop anticancer drugs for combating the resistance of current Smo inhibitors.
format Online
Article
Text
id pubmed-6274431
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-62744312018-12-28 Solasonine, A Natural Glycoalkaloid Compound, Inhibits Gli-Mediated Transcriptional Activity Yang, Jun Huang, Wenjing Tan, Wenfu Molecules Article The major obstacle limiting the efficacy of current Smoothened (Smo) inhibitors is the primary and acquired resistance mainly caused by Smo mutations and Gli amplification. In this context, developing Hh inhibitors targeting Gli, the final effector of this signaling pathway, may combat the resistance. In this study we found that solasonine, a natural glycoalkaloid compound, significantly inhibited the hedgehog (Hh) pathway activity. Meanwhile, solasonine may obviously inhibit the alkaline phosphatase (ALP) activity in C3H10T1/2 cells, concomitantly with reductions of the mRNA expression of Gli1 and Ptch1. However, we found that solasonine exhibited no effect on the transcriptional factors activities provoked by TNF-α and PGE2, thus suggesting its selectivity against Hh pathway activity. Furthermore, we identified that solasonine inhibited the Hh pathway activity by acting on its transcriptional factor Gli using a series of complementary data. We also observed that solasonine obviously inhibited the Gli-luciferase activity provoked by ectopic expression of Smo mutants which may cause the resistance to the current Smo inhibitors. Our study suggests that solasonine may significantly inhibit the Hh pathway activity by acting on Gli, therefore indicating the possibility to use solasonine as a lead compound to develop anticancer drugs for combating the resistance of current Smo inhibitors. MDPI 2016-10-14 /pmc/articles/PMC6274431/ /pubmed/27754442 http://dx.doi.org/10.3390/molecules21101364 Text en © 2016 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yang, Jun
Huang, Wenjing
Tan, Wenfu
Solasonine, A Natural Glycoalkaloid Compound, Inhibits Gli-Mediated Transcriptional Activity
title Solasonine, A Natural Glycoalkaloid Compound, Inhibits Gli-Mediated Transcriptional Activity
title_full Solasonine, A Natural Glycoalkaloid Compound, Inhibits Gli-Mediated Transcriptional Activity
title_fullStr Solasonine, A Natural Glycoalkaloid Compound, Inhibits Gli-Mediated Transcriptional Activity
title_full_unstemmed Solasonine, A Natural Glycoalkaloid Compound, Inhibits Gli-Mediated Transcriptional Activity
title_short Solasonine, A Natural Glycoalkaloid Compound, Inhibits Gli-Mediated Transcriptional Activity
title_sort solasonine, a natural glycoalkaloid compound, inhibits gli-mediated transcriptional activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274431/
https://www.ncbi.nlm.nih.gov/pubmed/27754442
http://dx.doi.org/10.3390/molecules21101364
work_keys_str_mv AT yangjun solasonineanaturalglycoalkaloidcompoundinhibitsglimediatedtranscriptionalactivity
AT huangwenjing solasonineanaturalglycoalkaloidcompoundinhibitsglimediatedtranscriptionalactivity
AT tanwenfu solasonineanaturalglycoalkaloidcompoundinhibitsglimediatedtranscriptionalactivity