Parthenolide sensitizes ultraviolet (UV)-B-induced apoptosis via protein kinase C-dependent pathways

Abstract

Parthenolide (PN) is the principal sesquiterpene lactone in feverfew (Tanacetum parthenium) with proven anti-inflammatory properties. We have previously reported that PN possesses strong anticancer activity in ultraviolet B (UVB)-induced skin cancer in SKH-1 hairless mice. In order to further understand the mechanism(s) involved in the anticancer activity of PN, we investigated the role of protein kinase C (PKC) in the sensitization activity of PN on UVB-induced apoptosis. Several subtypes of PKC have been reported to be involved in UVB-induced signaling cascade with both pro- and anti-apoptotic activities. Here we focused on two isoforms of PKC: novel PKCδ and atypical PKCζ. In JB6 murine epidermal cells, UVB induces the membrane translocations of both PKCs, and PN pre-treatment enhances the membrane translocation of PKCδ, but inhibits the translocation of PKCζ. Similar results were also detected when the activities of these PKCs were tested with the PKC kinase assay. Moreover, pre-treatment with a specific PKCδ inhibitor, rotterlin, completely diminishes the sensitization effect of PN on UVB-induced apoptosis. When cells were transiently transfected with dominant negative PKCδ or wild-type PKCζ, the sensitization effect of PN on UVB-induced apoptosis was also drastically reduced. Further mechanistic study revealed that PKCζ, but not PKCδ, is required for UVB-induced p38 MAPK activation and PN is likely to act through PKCζ to suppress p38 activation in UVB-treated JB6 cells. In conclusion, we demonstrated that PN sensitizes UVB-induced apoptosis via PKC-dependent pathways. © Oxford University Press 2005; all rights reserved.