Physalin H from Solanum nigrum as an Hh signaling inhibitor blocks GLI1–DNA-complex formation

Midori A Arai,Firoj Ahmed,Masami Ishibashi,Kyoko Uchida,Samir K Sadhu

doi:10.3762/bjoc.10.10

Midori A Arai, Firoj Ahmed + Show 3 more

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https://doi.org/10.3762/bjoc.10.10

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Abstract

Hedgehog (Hh) signaling plays an important role in embryonic development, cell maintenance and cell proliferation. Moreover, Hh signaling contributes to the growth of cancer cells. Physalins are highly oxidized natural products with a complex structure. Physalins (1–7) were isolated from Solanum nigrum (Solanaceae) collected in Bangladesh by using our cell-based assay. The isolated physalins included the previously reported Hh inhibitors 5 and 6. Compounds 1 and 4 showed strong inhibition of GLI1 transcriptional activity, and exhibited cytotoxicity against cancer cell lines with an aberrant activation of Hh signaling. Compound 1 inhibited the production of the Hh-related proteins patched (PTCH) and BCL2. Analysis of the structures of different physalins showed that the left part of the physalins was important for Hh inhibitory activity. Interestingly, physalin H (1) disrupted GLI1 binding to its DNA binding domain, while the weak inhibitor physalin G (2) did not show inhibition of GLI1-DNA complex formation.

Highlights

Hedgehog (Hh) signaling plays an important role in embryonic development and adult tissue maintenance [1,2]
Physalin H (1) inhibited GLI1 binding to its DNA binding domain as assessed by our previously reported electrophoresis mobility shift assay (EMSA)
We reported the first small molecule, which directly inhibits the GLI1–DNA complex formation [22].GANT61, a synthetic compound, has been reported to inhibit the GLI1–DNA-complex formation after cells were treated with this compound

Summary

Introduction

Hedgehog (Hh) signaling plays an important role in embryonic development and adult tissue maintenance [1,2]. We evaluated the Hh inhibitory activity by assessing the cytotoxicity against cancer cells and the expression of Hh-related proteins. Physalin H (1) inhibited GLI1 binding to its DNA binding domain as assessed by our previously reported electrophoresis mobility shift assay (EMSA).

Results

Conclusion