Perifosine sensitizes UVB-induced apoptosis in skin cells: New implication of skin cancer prevention?

We demonstrate here that a relative low dose of perifosine significantly enhanced UVB-induced apoptosis in skin cells (keratinocytes and fibroblasts), associated with a significant increase of reactive oxygen species (ROS) and ceramide production as well as multiple perturbations of diverse cell sig...

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Bibliographic Details
Published in:Cellular signalling 2012-09, Vol.24 (9), p.1781-1789
Main Authors: Ji, Chao, Yang, Yan-li, Yang, Zhi, Tu, Ying, Cheng, Lei, Chen, Bin, Xia, Ji-ping, Sun, Wei-ling, Su, Zhong-lan, He, Li, Bi, Zhi-gang
Format: Article
Language:English
Subjects:
Apoptosis
Apoptosis - drug effects
Apoptosis - radiation effects
Cells, Cultured
Ceramides - biosynthesis
Dose-Response Relationship, Drug
Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors
Extracellular Signal-Regulated MAP Kinases - metabolism
Humans
Perifosine
Phosphorylcholine - analogs & derivatives
Phosphorylcholine - pharmacology
Proto-Oncogene Proteins c-akt - antagonists & inhibitors
Proto-Oncogene Proteins c-akt - metabolism
Reactive Oxygen Species - metabolism
Signal transduction
Signal Transduction - drug effects
Skin - cytology
Skin - drug effects
Skin cancer
Skin Neoplasms - prevention & control
Structure-Activity Relationship
Ultraviolet Rays
UV radiation
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Summary:We demonstrate here that a relative low dose of perifosine significantly enhanced UVB-induced apoptosis in skin cells (keratinocytes and fibroblasts), associated with a significant increase of reactive oxygen species (ROS) and ceramide production as well as multiple perturbations of diverse cell signaling pathways, shifting to a significant pro-apoptosis outcomes. Perifosine inhibited UVB-induced pro-survival Akt/mammalian target of rapamycin (mTOR) and ERK activation, while facilitating pro-apoptotic AMP-activated protein kinas (AMPK), c-Jun-NH2-kinase (JNK), and p53 activation; these signaling changes together promoted a striking increase in skin cell apoptosis and a significantly reduced amount of DNA damages. Our results suggest that perifosine may represent a novel skin cancer prevention strategy. ► Perifosine significantly enhances UVB-induced skin cell apoptosis. ► Perifosine inhibits UVB-induced Akt/mTOR and ERK/MAPK activation. ► Perifosine facilitates UVB-induced ROS and ceramide production to activate AMPK. ► Activation of AMPK promotes JNK activation in UVB and perifosine treated skin cells. ► Perifosine increases UVB-induced p53 activation to limit DNA damage.
ISSN:0898-6568
1873-3913
DOI:10.1016/j.cellsig.2012.05.003