Molecular pathways involved in the anti‐apoptotic effect of 1,25‐dihydroxyvitamin D₃ in primary human keratinocytes

Abstract

We previously reported that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] protects primary human keratinocytes against ultraviolet (UV)B-induced apoptosis. Here, we confirmed the anti-apoptotic effect of 1,25(OH)2D3 in keratinocytes, using cisplatin and doxorubicin as apoptotic triggers. We further showed that 1,25(OH)2D3 activates two survival pathways in keratinocytes: the MEK/extracellular signal regulated kinase (ERK) and the phosphatidylinositol 3-kinase (PI-3K)/Akt pathway. Activation of ERK and Akt by 1,25(OH)2D3 was transient, required a minimal dose of 10(-9) M and could be blocked by actinomycin D and cycloheximide. Moreover, inhibition of Akt or ERK activity with respectively a PI-3K inhibitor (LY294002) or MEK inhibitors (PD98059, UO126), partially or totally suppressed the anti-apoptotic capacity of 1,25(OH)2D3. Finally, 1,25(OH)2D3 changed the expression of different apoptosis regulators belonging to the Bcl-2 family. Indeed, 1,25(OH)2D3 treatment increased levels of the anti-apoptotic protein Bcl-2 and decreased levels of the pro-apoptotic proteins Bax and Bad in a time- and dose-dependent way. Induction of Bcl-2 by 1,25(OH)2D3 was further shown to be mediated by ERK and, to a lesser extent, by Akt. In conclusion, 1,25(OH)2D3 clearly protects keratinocytes against apoptosis (1) by activating the MEK/ERK and the PI-3K/Akt survival pathways and (2) by increasing the Bcl-2 to Bax and Bad ratio.

AKT Pathway is Activated by 1,25-Dihydroxyvitamin D3 and Participates in its Anti-Apoptotic Effect and Cell Cycle Control in Differentiating HL60 Cells

“…26,27 Similarly, 1,25D was reported to have an anti-apoptotic effect in primary human keratinocytes, which was accompanied by a transient activation of AKT. 5 The effects of 1,25D on AKT activity are clearly cell contextdependent, as in this study we found 1,25D-induced activation not to be transient, but increasing for at least 48 h (Fig. 1).…”

“…Thus, it is not surprising that differentiation inducing agents such as erythropoietin also have an anti-apoptotic effect on the maturing erythroid cells. 1 Also, androgens are known to be major growth and survival factors for normal prostate cells, 2 while the vitamin/ hormone 1,25-dihydroxyvitamin D 3 (1,25D) induces both differentiation and increased survival of several types of cells, including hematopoietic cells, 3,4 primary human keratinocytes, 5 and murine osteoblastic cells. 6 While increased survival is a desirable feature of normal differentiating cells, it may confound the design of differentiation therapy for neoplastic diseases.…”

Vitamin D and the Pathophysiology of Inflammatory Skin Diseases

“…The antiapoptotic or cytoprotective effect of vitamin D is shown to be mediated by sphinosine-1-phosphate. Other mechanisms are also reported to be responsible for the antiapoptotic effect of vitamin D like the activation of MEK/ERK and PI3K/Akt signaling pathways, and the increased ratio of antiapoptotic protein (Bcl-2) to proapoptotic protein (Bad and Bax) [25]. …”

Vitamin D und Haut

“…Schritt ist die Bildung von 7-Dehydrocholesterin (7-DHC = Provitamin D 3 ) aus Squalen. In der Haut wird 7-DHC abgelagert und durch ultraviolette (UV-)Strahlung zunächst in Prävitamin D 3 Seit einigen Jahren ist bekannt, dass epidermale Keratinozyten ebenfalls die Enzyme 1α-OH-, 25OH-und 24OHase aufweisen, die ihnen die autonome 7 UVB-induzierte Synthese von 1,25(OH) 2 D 3 aus 7-DHC ermöglichen [13,15]. Weiter können Keratinozyten aus 25(OH)D 3 , 1α-OHD 3 und aus D 3 1,25(OH) 2 D 3 synthetisieren [17].…”

“…Bei Vorgängen wie Zellproliferation, Zelldifferenzierung, Immunprozessen und Apoptose spielen eine etwaige Über-oder Unterversorgung mit Vitamin D und dessen Metaboliten eine besondere Rolle für pathophysiologische Prozesse des gesamten Organismus einerseits, aber auch für die Haut im Speziellen [19,3]. Einzelne Arbeiten beschreiben sogar, dass eine Sonnenexposition unter Vermeidung eines Sonnenbrandes das Risiko für eine Karzinomentstehung senken kann, ohne das Risiko für Hauttumoren zu erhöhen [6].…”