Journal
INTERNATIONAL JOURNAL OF ONCOLOGY
Volume 41, Issue 6, Pages 2191-2199Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2012.1664
Keywords
wedelolactone; 5-lipoxygenase; protein kinase C epsilon; prostate cancer; apoptosis
Categories
Funding
- National Cancer Institute of the National Institutes of Health [RO1 CA 152334]
- Department of Defense Prostate Cancer Research Program [W81-XWH-05-1-0022]
- Henry Ford Health System internal grant [A10203]
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Emerging studies indicate that metabolism of arachidonic acid through the 5-lipoxygenase (5-Lox) pathway plays a critical role in the survival of prostate cancer cells raising the possibility that 5-Lox can be targeted for an effective therapy of prostate cancer. Wedelolactone (WDL), a medicinal plant-derived natural compound, is known to inhibit 5-Lox activity in neutrophils. However, its effect on apoptosis in prostate cancer cells has not been addressed. Thus, we tested the effects of WDL on human prostate cancer cells in vitro. We observed that WDL kills both androgen-sensitive as well as androgen-independent prostate cancer cells in a dose-dependent manner by dramatically inducing apoptosis. We also found that WDL-induced apoptosis in prostate cancer cells is dependent on c-Jun N-terminal Kinase (c-JNK) and caspase-3. Interestingly, WDL triggers apoptosis in prostate cancer cells via downregulation of protein kinase C epsilon (PKC epsilon), but without inhibition of Akt. WDL does not affect the viability of normal prostate epithelial cells (PrEC) at doses that kill prostate cancer cells, and WDL-induced apoptosis is effectively prevented by 5-oxoETE, a metabolite of 5-Lox (but not by 15-oxoETE, a metabolite of 15-Lox), suggesting that the apoptosis-inducing effect of WDL in prostate cancer cells is mediated via inhibition of 5-Lox activity. These findings indicate that WDL selectivity induces caspase-dependent apoptosis in prostate cancer cells via a novel mechanism involving inhibition of PKC epsilon without affecting Akt and suggest that WDL may emerge as a novel therapeutic agent against clinical prostate cancer in human.
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