Retinoic acid modulates the anti-proliferative effect of 1,25-dihydroxyvitamin D3 in cultured human epidermal keratinocytes.
Both 1,25-dihydroxyvitamin D3 (VD) and retinoids have potent effects on keratinocyte proliferation. Parallelism in their action as steroid hormones, which involves interaction of their receptors, and in their therapeutic efficacy for hyper-proliferative skin diseases provides a rationale to investigate their combined action on proliferation in pre-confluent human epidermal keratinocyte cultures. As shown by [3H]thymidine incorporation, all-trans retinoic acid (atRA) at subpharmacologic concentrations and 9-cis retinoic acid (9cRA) diminished the anti-proliferative effect of VD. Pre-incubation of the cells with the retinoids clearly enhanced this effect. Cell-cycle analysis revealed G1 arrest upon VD treatment that was attenuated by retinoic acid (RA). Moreover, Northern and Western blot analysis demonstrated that retinoic acid opposed VD-induced accumulation of transforming growth factor-beta1, p21WAF1, and p27KIP1. Finally, retinoic acid reduced VD-elicited hypophosphorylation of the retinoblastoma protein. AtRA at micromolar concentrations conversely potentiated most of the aforementioned VD-dependent actions. In addition, atRA and 9cRA (but not VD) caused a rapid, sustained reduction of RXR alpha protein. VD receptor protein was induced by VD regardless of the presence of RA. In conclusion, RA modulates VD-dependent effects at different levels of keratinocyte proliferation. This could have implications for the use of combinations of both drugs for skin diseases.
Segaert
S
S
Department of Dermatology, Gasthuisberg, Katholieke Universiteit Leuven, Belgium.
Garmyn
M
M
Degreef
H
H
Bouillon
R
R
D002117:Calcitriol / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D016213:Cyclins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000737:chemistry / Q000166:cytology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010766:Phosphorylation; D018167:Receptors, Calcitriol / Q000187:drug effects / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000378:metabolism; D012175:Retinoblastoma / Q000378:metabolism; D047488:Retinoid X Receptors; D012176:Retinoids / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D014316:Tritium; D025521:Tumor Suppressor Proteins
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D014316:Tritium; D050760:Cyclin-Dependent Kinase Inhibitor p27; D014212:Tretinoin; D018844:Cyclin-Dependent Kinases; D002117:Calcitriol; D013936:Thymidine