1α,25-Dihydroxyvitamin-D3-3-Bromoacetate Regulates AKT/mTOR Signaling Cascades: A Therapeutic Agent for Psoriasis
| Autor: | Rebecca Wright, Ananya Datta Mitra, Anupam Mitra, Rahul Ray, Siba P. Raychaudhuri, Christine Abria, Smriti Kundu-Raychaudhuri |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Keratinocytes
S100A7 Cell Survival Gene Expression AKT1 Apoptosis Dermatology Biology Biochemistry S100 Calcium Binding Protein A7 03 medical and health sciences 0302 clinical medicine Calcitriol Annexin Humans Psoriasis Phosphorylation Vitamin D Protein kinase A Chemokine CCL5 Protein kinase B Molecular Biology Cells Cultured PI3K/AKT/mTOR pathway Cell Proliferation 030304 developmental biology 0303 health sciences Interleukins TOR Serine-Threonine Kinases Interleukin-8 S100 Proteins Vitamins Cell Biology Molecular biology 3. Good health Epidermal Cells 030220 oncology & carcinogenesis Cancer research Signal transduction Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Journal of Investigative Dermatology. 133(6):1556-1564 |
| ISSN: | 0022-202X |
| DOI: | 10.1038/jid.2013.3 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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