Parthenolide sensitizes ultraviolet (UV)-B-induced apoptosis via protein kinase C-dependent pathways.
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 PKCdelta and atypical PKCzeta. In JB6 murine epidermal cells, UVB induces the membrane translocations of both PKCs, and PN pre-treatment enhances the membrane translocation of PKCdelta, but inhibits the translocation of PKCzeta. Similar results were also detected when the activities of these PKCs were tested with the PKC kinase assay. Moreover, pre-treatment with a specific PKCdelta inhibitor, rotterlin, completely diminishes the sensitization effect of PN on UVB-induced apoptosis. When cells were transiently transfected with dominant negative PKCdelta or wild-type PKCzeta, the sensitization effect of PN on UVB-induced apoptosis was also drastically reduced. Further mechanistic study revealed that PKCzeta, but not PKCdelta, is required for UVB-induced p38 MAPK activation and PN is likely to act through PKCzeta to suppress p38 activation in UVB-treated JB6 cells. In conclusion, we demonstrated that PN sensitizes UVB-induced apoptosis via PKC-dependent pathways.
Won
Yen-Kim
YK
Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Republic of Singapore.
Ong
Choon-Nam
CN
Shen
Han-Ming
HM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects / Q000528:radiation effects; D005799:Genes, Dominant; D051379:Mice; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099221:Protein Kinase C zeta
D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D012717:Sesquiterpenes; D048051:p38 Mitogen-Activated Protein Kinases; D000099221:Protein Kinase C zeta; C002669:parthenolide