Azadirachtin interacts with retinoic acid receptors and inhibits retinoic acid-mediated biological responses

Maikho Thoh, Banaganapalli Babajan, Pongali B. Raghavendra, Chitta Sureshkumar, Sunil K. Manna

Research output: Contribution to journalArticle

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Abstract

Considering the role of retinoids in regulation of more than 500 genes involved in cell cycle and growth arrest, a detailed understanding of the mechanism and its regulation is useful for therapy. The extract of the medicinal plant Neem (Azadirachta indica) is used against several ailments especially for anti-inflammatory, anti-itching, spermicidal, anticancer, and insecticidal activities. In this report we prove the detailed mechanism on the regulation of retinoic acid-mediated cell signaling by azadirachtin, active components of neem extract. Azadirachtin repressed all trans-retinoic acid (ATRA)-mediated nuclear transcription factor κB (NF-κB) activation, not the DNA binding but the NF-κB-dependent gene expression. It did not inhibit IκBα degradation, IκBα kinase activity, or p65 phosphorylation and its nuclear translocation but inhibited NF-κB-dependent reporter gene expression. Azadirachtin inhibited TRAF6-mediated, but not TRAF2-mediated NF-κB activation. It inhibited ATRA-induced Sp1 and CREB (cAMP-response element-binding protein) DNA binding. Azadirachtin inhibited ATRA binding with retinoid receptors, which is supported by biochemical and in silico evidences. Azadirachtin showed strong interaction with retinoid receptors. It suppressed ATRA-mediated removal of retinoid receptors, bound with DNA by inhibiting ATRA binding to its receptors. Overall, our data suggest that azadirachtin interacts with retinoic acid receptors and suppresses ATRA binding, inhibits falling off the receptors, and activates transcription factors like CREB, Sp1, NF-κB, etc. Thus, azadirachtin exerts anti-inflammatory and anti-metastatic responses by a novel pathway that would be beneficial for further anti-inflammatory and anti-cancer therapies.

Original languageEnglish
Pages (from-to)4690-4702
Number of pages13
JournalJournal of Biological Chemistry
Volume286
Issue number6
DOIs
Publication statusPublished - 11-02-2011

Fingerprint

Retinoic Acid Receptors
Tretinoin
Transcription Factors
Retinoids
Cyclic AMP Response Element-Binding Protein
Anti-Inflammatory Agents
Gene expression
DNA
TNF Receptor-Associated Factor 2
Chemical activation
TNF Receptor-Associated Factor 6
Azadirachta
Sp1 Transcription Factor
Cell signaling
Gene Expression
Phosphorylation
Pruritus
Medicinal Plants
Cell Cycle Checkpoints
azadirachtin

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Thoh, Maikho ; Babajan, Banaganapalli ; Raghavendra, Pongali B. ; Sureshkumar, Chitta ; Manna, Sunil K. / Azadirachtin interacts with retinoic acid receptors and inhibits retinoic acid-mediated biological responses. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 6. pp. 4690-4702.
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Azadirachtin interacts with retinoic acid receptors and inhibits retinoic acid-mediated biological responses. / Thoh, Maikho; Babajan, Banaganapalli; Raghavendra, Pongali B.; Sureshkumar, Chitta; Manna, Sunil K.

In: Journal of Biological Chemistry, Vol. 286, No. 6, 11.02.2011, p. 4690-4702.

Research output: Contribution to journalArticle

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