期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
卷 1813, 期 12, 页码 2108-2117出版社
ELSEVIER
DOI: 10.1016/j.bbamcr.2011.07.015
关键词
5-Lipoxygenase; Prostate cancer; Apoptosis; PKC-epsilon
资金
- United States Department [DAMD 17-02-1-0153, W81XWH-05-1-0022]
- Henry Ford Health System [A-10203]
Previous studies have shown that human prostate cancer cells constitutively generate 5-lipoxygenase (5-LOX) metabolites from arachidonic acid, and inhibition of 5-LOX blocks production of 5-LOX metabolites and triggers apoptosis in prostate cancer cells. This apoptosis is prevented by exogenous metabolites of 5-LOX, suggesting an essential role of 5-LOX metabolites in the survival of prostate cancer cells. However, downstream signaling mechanisms which mediate the survival-promoting effects of 5-LOX metabolites in prostate cancer cells are still unknown. Recently, we reported that MK591, a specific inhibitor of 5-LOX activity, induces apoptosis in prostate cancer cells without inhibition of Akt, or ERK, two well-characterized regulators of pro-survival mechanisms, suggesting the existence of an Akt and ERK-independent survival mechanism in prostate cancer cells regulated by 5-LOX. Here, we report that 5-LOX inhibition-induced apoptosis in prostate cancer cells occurs via rapid inactivation of protein kinase C-epsilon (PKC epsilon), and that exogenous 5-LOX metabolites prevent both 5-LOX inhibition-induced down-regulation of PKC epsilon and induction of apoptosis. Interestingly, pre-treatment of prostate cancer cells with diazoxide (a chemical activator of PKC epsilon), or KAE1-1 (a cell-permeable, octa-peptide specific activator of PKC epsilon) prevents 5-LOX inhibition-induced apoptosis, which indicates that inhibition of 5-LOX triggers apoptosis in prostate cancer cells via down-regulation of PKC epsilon. Altogether, these findings suggest that metabolism of arachidonic acid by 5-LOX activity promotes survival of prostate cancer cells via signaling through PKC epsilon, a pro-survival serine/threonine kinase. (C) 2011 Elsevier B.V. All rights reserved.
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