Low-dose UV-radiation sensitizes keratinocytes to TRAIL-induced apoptosis

Abstract

The impact of low‐dose ultraviolet light (UV‐light) on apoptotic susceptibility of keratinocytes (KCs) induced by TRAIL is unclear. Skin expresses a functional form of TRAIL, and while sun exposure influences TRAIL death receptors, a role for decoy receptors has not been evaluated. Unraveling mechanisms involving apoptotic sensitivity of KCs is important because skin is the first target of UV‐light, and a site for commonly occurring cancers. Since apoptosis is a homeostatic process eliminating UV‐light induced DNA damaged cells, elucidating molecular events regulating apoptosis enhances understanding of cutaneous photocarcinogenesis. Here we demonstrate low‐dose UV‐light enhances susceptibility of KCs to TRAIL‐induced apoptosis. Low‐dose UV‐light selectively reduces decoy receptors, without influencing death receptor levels. UV‐induced enhanced apoptotic susceptibility was reduced by over‐expression of decoy receptor TRAIL‐R4, but not TRAIL‐R3; or treatment with thiol compound pyrrolidine dithiocarbamate (PDTC), which also enhanced TRAIL‐R4 levels. Besides influencing decoy receptors, low‐dose UV‐light plus TRAIL also synergistically promoted cytochrome c and Smac release from mitochondria. Inhibitors directed against caspases 2, 3, 8, and 9 reduced the synergistic apoptotic response following low‐dose UV‐light plus TRAIL exposure; as did forced over‐expression of Bcl‐x and dominant negative (DN) constructs of FADD and caspase 9. Thus, relative levels of decoy receptors significantly influence susceptibility of KCs to TRAIL‐induced apoptosis with concomitant low‐dose UV‐light exposure; in addition to the apoptotic pathway mediated by mitochondrial permeabilization. © 2004 Wiley‐Liss, Inc.