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.
Highlights
The Hedgehog (Hh) signaling pathway, an evolutionarily conserved signaling axis, plays critical roles in various physiological and pathological conditions, such as embryonic patterning, tissue homeostasis, and cancer [1,2]
Prostaglandin E2 (PGE2) obviously stimulated the CM,(Figure we examined the effect of solasonine on the activity of other transcriptional factors, CM, we3A), nextand examined the effect of solasonine the activity of other transcriptional such assuch luciferase activity on
The results showed that solasonine significantly suppressed the Hh pathway activity caused by via lentivirus mediated in NIH-3T3 cellsin
Summary
The Hedgehog (Hh) signaling pathway, an evolutionarily conserved signaling axis, plays critical roles in various physiological and pathological conditions, such as embryonic patterning, tissue homeostasis, and cancer [1,2]. The binding of Hh ligands to ptch, a 12-transmembrane cell surface receptor, may relieve the inhibitory effect of ptch on Smoothened (Smo), a member of the. This allows the accumulation of Smo in the primary cilium. Canonical Hh signaling regulates the activity, proteolytic processing, and the stability of the Gli family transcriptional factors, Gli, and subsequently initiates the transcription of Gli-dependent target genes, such as Gli and ptch. Canonical Hh signaling regulates the activity, proteolytic processing, and the stability of the Gli family transcriptional factors, Gli, and subsequently initiates the transcription of Gli-dependent target genes, such as Gli and ptch1 This regulation involves a number of protein kinases, including protein kinase A (PKA), glycogen synthase kinase 3 (GSK3) and case kinase 1, and the negative regulator suppressor of fused (SuFu) [2]
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