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Solasonine, A Natural Glycoalkaloid Compound, Inhibits Gli-Mediated Transcriptional Activity.
- Source :
-
Molecules (Basel, Switzerland) [Molecules] 2016 Oct 14; Vol. 21 (10). Date of Electronic Publication: 2016 Oct 14. - Publication Year :
- 2016
-
Abstract
- 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.
- Subjects :
- Alkaline Phosphatase metabolism
Animals
Cell Line
Gene Expression Regulation drug effects
HEK293 Cells
Hedgehog Proteins genetics
Hedgehog Proteins metabolism
Humans
Mice
NIH 3T3 Cells
Patched-1 Receptor genetics
Signal Transduction drug effects
Zinc Finger Protein GLI1 metabolism
Solanaceous Alkaloids pharmacology
Transcription, Genetic drug effects
Zinc Finger Protein GLI1 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1420-3049
- Volume :
- 21
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Molecules (Basel, Switzerland)
- Publication Type :
- Academic Journal
- Accession number :
- 27754442
- Full Text :
- https://doi.org/10.3390/molecules21101364