Abstract 2253: Wedelolactone, a medicinal plant-derived coumestan, induces caspase-dependent apoptosis in prostate cancer cells via down-regulation of PKC-epsilon without inhibiting Akt.

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Abstract Background: Prostate cancer cells continuously generate 5(S)-HETE series of metabolites via 5-lipoxygenase (5-Lox) activity, and inhibition of 5-Lox blocks production of metabolites and triggers apoptosis both in androgen-sensitive and androgen-independent prostate cancer cells. Apoptosis is prevented by 5(S)-HETE and 5-oxoETE, but not by leukotrienes or metabolites of 12-Lox or 15-Lox, which is consistent with the idea that the 5-HETE series of metabolites are essential survival factors for prostate cancer cells. Recently, we found that 5-Lox-regulated survival-signaling is mediated via protein kinase C-epsilon (PKCε), but not Akt, or ERK. Prostate tumor tissues express high levels of 5-Lox, but the expression of 5-Lox in normal prostate glands is undetectable. Thus, 5-Lox emerges as a novel molecular target for prostate cancer therapy. However, lack of suitable 5-Lox inhibitors for in vivo use is hampering progress towards clinical development. Several natural compounds possess 5-Lox inhibitory effects, raising the possibility that effective 5-Lox inhibitors may be found in natural products for use against prostate cancer. Wedelolactone (WDL), a medicinal plant-derived coumestan, is known to inhibit 5-Lox activity in neutrophils. However, its potential on apoptosis induction in prostate cancer cells is not known. Thus, we tested the effects of WDL on a range of human prostate cancer cells in vitro. Methods: Prostate cancer cells were treated with doses of WDL for varying periods of time. Apoptosis was measured by annexin-V binding, PARP-cleavage, and DNA-degradation. Role of caspase in apoptosis was tested by enzymatic assays and chemical inhibitors. Effects of WDL on PKC-epsilon and Akt were analyzed by Western blot and enzymatic assays. Results: 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. This apoptosis is dependent on c-Jun N-terminal Kinase (c-JNK) and caspase-3. Interestingly, WDL was observed to trigger apoptosis in prostate cancer cells via down-regulation of protein kinase C-epsilon (PKCε), but without any inhibition of Akt. WDL does not affect the viability of normal prostate epithelial cells (PrEC) at doses that kill prostate cancer cells. Moreover, it was found that WDL-induced apoptosis is effectively prevented by 5-oxoETE, a metabolite of 5-Lox, confirming that WDL induces apoptosis in prostate cancer cells via inhibition of 5-Lox activity. Conclusion: Our findings indicate that WDL selectivity induces caspase-dependent apoptosis in prostate cancer cells via a novel mechanism involving inhibition of the oncogenic serine/threonine kinase PKCε without affecting Akt, and suggest that WDL may emerge as a novel therapeutic agent against clinical prostate cancer in human. Citation Format: Sivalokanathan Sarveswaran, Subhash Gautam, Jagadananda Ghosh. Wedelolactone, a medicinal plant-derived coumestan, induces caspase-dependent apoptosis in prostate cancer cells via down-regulation of PKC-epsilon without inhibiting Akt. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2253. doi:10.1158/1538-7445.AM2013-2253