Inhibition of 5-lipoxygenase triggers apoptosis in prostate cancer cells via down-regulation of protein kinase C-epsilon.

Abstract

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 (PKCε), and that exogenous 5-LOX metabolites prevent both 5-LOX inhibition-induced down-regulation of PKCε and induction of apoptosis. Interestingly, pre-treatment of prostate cancer cells with diazoxide (a chemical activator of PKCε), or KAE1-1 (a cell-permeable, octa-peptide specific activator of PKCε) prevents 5-LOX inhibition-induced apoptosis, which indicates that inhibition of 5-LOX triggers apoptosis in prostate cancer cells via down-regulation of PKCε. Altogether, these findings suggest that metabolism of arachidonic acid by 5-LOX activity promotes survival of prostate cancer cells via signaling through PKCε, a pro-survival serine/threonine kinase.

• Authors: Sivalokanathan Sarveswaran, Vijayalakshmi Thamilselvan, Chaya Brodie, Jagadananda Ghosh
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1813 Issue 12 Pg. 2108-17 (Dec 2011) ISSN: 0006-3002 [Print] Netherlands
• PMID: 21824498 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• Eicosanoids
• Lipoxygenase Inhibitors
• Arachidonate 5-Lipoxygenase
• Proto-Oncogene Proteins c-akt
• Protein Kinase C-epsilon

Topics

• Apoptosis
• Arachidonate 5-Lipoxygenase (metabolism)
• Blotting, Western
• Down-Regulation
• Eicosanoids (pharmacology)
• Flow Cytometry
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immunoprecipitation
• Lipoxygenase Inhibitors (pharmacology)
• Male
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Protein Kinase C-epsilon (antagonists & inhibitors)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• Tumor Cells, Cultured