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

29 Citations (Scopus)

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

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Sirolimus
Psoriasis
Keratinocytes
Epidermis
Antimitotic Agents
Therapeutics
Signal transduction
Phosphorylation
T-cells
Immunomodulation
Calcitriol
Annexin A5
Protein-Serine-Threonine Kinases
Fluorescein
Interleukin-8
Chemokines
Gene expression
Dilution
Real-Time Polymerase Chain Reaction
Assays

ASJC Scopus subject areas

  • Dermatology
  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

1α,25-dihydroxyvitamin-D3-3-bromoacetate regulates AKT/mTOR signaling cascades : A therapeutic agent for psoriasis. / Datta Mitra, Ananya; Raychaudhuri, Siba P; Abria, Christine J.; Mitra, Anupam; Wright, Rebecca; Ray, Rahul; Kundu-Raychaudhuri, Smriti.

In: Journal of Investigative Dermatology, Vol. 133, No. 6, 06.2013, p. 1556-1564.

Research output: Contribution to journalArticle

Datta Mitra, Ananya ; Raychaudhuri, Siba P ; Abria, Christine J. ; Mitra, Anupam ; Wright, Rebecca ; Ray, Rahul ; Kundu-Raychaudhuri, Smriti. / 1α,25-dihydroxyvitamin-D3-3-bromoacetate regulates AKT/mTOR signaling cascades : A therapeutic agent for psoriasis. In: Journal of Investigative Dermatology. 2013 ; Vol. 133, No. 6. pp. 1556-1564.
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