title: Solasonine, A Natural Glycoalkaloid Compound, Inhibits Gli-Mediated Transcriptional Activity.
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 ofGli1andPtch1. 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.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. 14211030042@fudan.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. 15211030052@fudan.edu.cn.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. wftan@fudan.edu.cn.
authors.forename: Wenfu
authors.initials: W
authors.lastname: Tan
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D000072081:Patched-1 Receptor / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D012991:Solanaceous Alkaloids / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*; D000071676:Zinc Finger Protein GLI1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins; D000072081:Patched-1 Receptor; D012991:Solanaceous Alkaloids; D000071676:Zinc Finger Protein GLI1; C026608:alpha-solamargine; D000469:Alkaline Phosphatase
keywords: Gli resistance; hedgehog; solasonine