Cucurbitacins are insect steroid hormone antagonists acting at the ecdysteroid receptor

Dinan, Laurence; Whiting, Pensri; Girault, Jean‐Pierre; Lafont, René; Dhadialla, S. Tarlochan; Cress, E. Dean; Mugat, Bruno; Antoniewski, Christophe; Lepesant, Jean‐Antoine

doi:10.1042/bj3270643

Cited by 99 publications

(78 citation statements)

References 32 publications

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“…We thus interfered with ecdysone signaling activity, using cucurbitacin B, an ecdysone receptor antagonist that prevents the binding of ecdysone (29). This compound has previously been used in butterflies to inhibit ecdysone signaling (27).…”

Section: Resultsmentioning

confidence: 99%

Ecdysone signaling underlies the pea aphid transgenerational wing polyphenism

Vellichirammal

Gupta

Hall

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

110

102

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The wing polyphenism of pea aphids is a compelling laboratory model with which to study the molecular mechanisms underlying phenotypic plasticity. In this polyphenism, environmental stressors such as high aphid density cause asexual, viviparous adult female aphids to alter the developmental fate of their embryos from wingless to winged morphs. This polyphenism is transgenerational, in that the pea aphid mother experiences the environmental signals, but it is her offspring that are affected. Previous research suggested that the steroid hormone ecdysone may play a role in this polyphenism. Here, we analyzed ecdysone-related gene expression patterns and found that they were consistent with a down-regulation of the ecdysone pathway being involved in the production of winged offspring. We therefore predicted that reduced ecdysone signaling would result in more winged offspring. Experimental injections of ecdysone or its analog resulted in a decreased production of winged offspring. Conversely, interfering with ecdysone signaling using an ecdysone receptor antagonist or knocking down the ecdysone receptor gene with RNAi resulted in an increased production of winged offspring. Our results are therefore consistent with the idea that ecdysone plays a causative role in the regulation of the proportion of winged offspring produced in response to crowding in this polyphenism. Our results also show that an environmentally regulated maternal hormone can mediate phenotype production in the next generation, as well as provide significant insight into the molecular mechanisms underlying the functioning of transgenerational phenotypic plasticity.

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Section: Resultsmentioning

confidence: 99%

Ecdysone signaling underlies the pea aphid transgenerational wing polyphenism

Vellichirammal

Gupta

Hall

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

110

102

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“…For example, the phytosteroid ajugalactone from Ajuga decumbens and the triterpene cucurbitacins that can be isolated from the candytuft (Iberis umbellata) are powerful antagonists of 20-hydroxyecdysone in molting assays, inhibiting the action of the hormone by competing for binding to its receptor (60,61). The development of these molecules as ecdysone-system antagonists could make the system more pulsatile.…”

Section: Discussionmentioning

confidence: 99%

Identification of ligands and coligands for the ecdysone-regulated gene switch

Sáez

Nelson

Eshelman

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

106

109

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The ecdysone-inducible gene switch is a useful tool for modulating gene expression in mammalian cells and transgenic animals. We have identified inducers derived from plants as well as certain classes of insecticides that increase the versatility of this gene regulation system. Phytoecdysteroids share the favorable kinetics of steroids, but are inert in mammals. The gene regulation properties of one of these ecdysteroids have been examined in cell culture and in newly developed strains of ecdysone-system transgenic mice. Ponasterone A is a potent regulator of gene expression in cells and transgenic animals, enabling reporter genes to be turned on and off rapidly. A number of nonsteroidal insecticides have been identified that also activate the ecdysone system. Because the gene-controlling properties of the ecdysone switch are based on a heterodimer composed of a modified ecdysone receptor (VgEcR) and the retinoid X receptor (RXR), we have tested the effect of RXR ligands on the VgEcR͞RXR complex. Used alone, RXR ligands display no activity on the ecdysone switch. However, when used in combination with a VgEcR ligand, RXR ligands dramatically enhance the absolute levels of induction. This property of the heterodimer has allowed the development of superinducer combinations that increase the dynamic range of the system.

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“…Cucurbitacins B and D (from Iberis umbellate) and various cucurbitane-like compounds (from Hemsleya carnosiflora), including dihydrocucurbitacin F and dihydrocucurbitacin F acetylated at C 25 , have been identified as antagonists to insect steroid hormones acting at the ecdysteroid (regulation of the pupation) receptor in Drosophila melanogaster cells cultured in vitro (Dinan et al, 1997a(Dinan et al, , 1997b. A 50% inhibition of hormone binding to the ecdysteroid receptor was obtained in the presence of 1.5 μM cucurbitacin B, 10 μM cucurbitacin D, and around 100 μM dihydrocucurbitacin F or 25-acetoxydihydrocucurbitacin F. Important chemical structural features for antagonistic activity on the receptor were the presence of a double bond between carbon atoms 23 and 24, a keto function at C 22 , and a sufficiently long side chain (Dinan et al 1997a).…”

Section: Delporte Et Al 2002mentioning

confidence: 99%

“…Cucurbitacin B and cucurbitacin D have been isolated from Iberis umbellata seeds (Dinan et al, 1997a).…”

Section: Cruciferaementioning

confidence: 99%