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Carcinogenesis Advance Access published online on July 28, 2005
Carcinogenesis, doi:10.1093/carcin/bgi194
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received March 17, 2005
Revised July 10, 2005
Accepted July 22, 2005

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

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

Yen-Kim Won 1, Choon-Nam Ong 1, and Han-Ming Shen 1*

1 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 correspondence should be addressed.
Han-Ming Shen, E-mail: cofshm{at}nus.edu.sg


  Abstract

Parthenolide is the principal sesquiterpene lactone in feverfew (Tanacetum parthenium) with proven anti-inflammatory property. We have previously reported that parthenolide possesses strong anti-cancer activity in UVB-induced skin cancer in SKH-1 hairless mice. In order to further understand the mechanism(s) involved in the anti-cancer activity of parthenolide, we investigated the role of protein kinase C (PKC) in the sensitization activity of parthenolide 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 parthenolide 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 parthenolide on UVB-induced apoptosis. When cells were transiently transfected with dominant negative PKC{delta} or wild type PKC{zeta}, the sensitization effect of parthenolide 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 parthenolide sensitizes UVB-induced apoptosis via PKC-dependent pathways.


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