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

✍ Scribed by Petra De Haes; Marjan Garmyn; Geert Carmeliet; Hugo Degreef; Katleen Vantieghem; Roger Bouillon; Siegfried Segaert

• Publisher: John Wiley and Sons
• Year: 2004
• Tongue: English
• Weight: 599 KB
• Volume: 93
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.20227

✦ Synopsis

We previously reported that 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] protects primary human keratinocytes against ultraviolet (UV)B-induced apoptosis. Here, we confirmed the anti-apoptotic effect of 1,25(OH) 2 D 3 in keratinocytes, using cisplatin and doxorubicin as apoptotic triggers. We further showed that 1,25(OH) 2 D 3 activates two survival pathways in keratinocytes: the MEK/extracellular signal regulated kinase (ERK) and the phosphatidylinositol 3kinase (PI-3K)/Akt pathway. Activation of ERK and Akt by 1,25(OH) 2 D 3 was transient, required a minimal dose of 10 À9 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) 2 D 3 . Finally, 1,25(OH) 2 D 3 changed the expression of different apoptosis regulators belonging to the Bcl-2 family. Indeed, 1,25(OH) 2 D 3 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) 2 D 3 was further shown to be mediated by ERK and, to a lesser extent, by Akt. In conclusion, 1,25(OH) 2 D 3 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.