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Carcinogenesis Advance Access originally published online on July 28, 2005
Carcinogenesis 2005 26(12):2149-2156; doi:10.1093/carcin/bgi194
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Carcinogenesis vol.26 no.12 © Oxford University Press 2005; all rights reserved.

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

Yen-Kim Won, Choon-Nam Ong and Han-Ming Shen *

Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117597, Republic of Singapore

* To whom the correspondence should be addressed. Tel: +65 6874 4998; Fax: +65 6779 1489; Email: cofshm{at}nus.edu.sg

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 PKC{delta} and atypical PKC{zeta}. In JB6 murine epidermal cells, UVB induces the membrane translocations of both PKCs, and PN pre-treatment enhances the membrane translocation of PKC{delta}, but inhibits the translocation of PKC{zeta}. Similar results were also detected when the activities of these PKCs were tested with the PKC kinase assay. Moreover, pre-treatment with a specific PKC{delta} inhibitor, rotterlin, completely diminishes the sensitization effect of PN on UVB-induced apoptosis. When cells were transiently transfected with dominant negative PKC{delta} or wild-type PKC{zeta}, the sensitization effect of PN on UVB-induced apoptosis was also drastically reduced. Further mechanistic study revealed that PKC{zeta}, but not PKC{delta}, is required for UVB-induced p38 MAPK activation and PN is likely to act through PKC{zeta} to suppress p38 activation in UVB-treated JB6 cells. In conclusion, we demonstrated that PN sensitizes UVB-induced apoptosis via PKC-dependent pathways.


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