1α,25-dihydroxyvitamin-D3-3-bromoacetate regulates AKT/mTOR signaling cascades: A therapeutic agent for psoriasis

Ananya Datta Mitra, Siba P Raychaudhuri, Christine J. Abria, Anupam Mitra, Rebecca Wright, Rahul Ray, Smriti Kundu-Raychaudhuri

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

The efficacy of 1α,25-dihydroxyvitamin D3 (Vit-D) limits its topical use despite its profound effects on cellular differentiation, proliferation, and immunomodulation. Therefore, in search for a more effective analog of Vit-D, in this study we have evaluated the antiproliferative and proapoptotic effects of 1α,25-dihydroxyvitamin D3-3-bromoacetate (BE). Proliferation and apoptosis studies in normal human epidermal keratinocytes (NHEKs) were conducted by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), CFSE (carboxy fluorescein succinimidyl ester) dilution, and Annexin V assays. Western blot analysis and real-time PCR were performed to determine its effect on signal transduction. A reconstructed human epidermis (RHE) model was used to further validate the therapeutic role of BE in psoriasis. BE was significantly more potent than an equivalent concentration of Vit-D in inhibiting growth and survival of human keratinocytes. The antimitotic effect was found to be due to the inhibition of phosphorylation of serine/threonine protein kinase (AKT) and its downstream target, mammalian target of rapamycin (mTOR). In the RHE model, BE reversed IL-22-induced psoriasiform changes more effectively than Vit-D. Interestingly, BE inhibited the IL-22-induced gene expression of AKT1, MTOR, chemokines [IL-8 and RANTES (regulated upon activation, normal T-cell expressed and secreted)], and psoriasin (S100A7) more significantly than Vit-D. These results suggest the potential of BE as a prospective therapeutic agent for psoriasis.

Original languageEnglish (US)
Pages (from-to)1556-1564
Number of pages9
JournalJournal of Investigative Dermatology
Volume133
Issue number6
DOIs
StatePublished - Jun 2013

ASJC Scopus subject areas

  • Dermatology
  • Biochemistry
  • Cell Biology
  • Molecular Biology

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