Abstract
Prostratin, a non-tumor promoting 12-deoxyphorbol ester, has been reported as a protein kinase C (PKC) activator and is shown to have anti-proliferative activity in certain cancer cell types. Here we show that GRC-2, a prostratin analogue isolated from Euphorbia grandicornis, is ten-fold more potent than prostratin for inhibiting the growth of human non-small cell lung cancer (NSCLC) A549 cells. Flow cytometry assay revealed that GRC-2 and prostratin inhibited cell cycle progression at the G2/M phase and induced apoptosis. The cytotoxic effect of GRC-2 and prostratin was accompanied by activation and nuclear translocation of PKC-δ and PKD as well as hyperactivation of extracellular signal-related kinase (ERK). Knockdown of either PKC-δ, PKD or ERK significantly protected A549 cancer cells from GRC-2- and prostratin-induced growth arrest as well as apoptosis. Taken together, our results have shown that prostratin and a more potent analogue GRC-2 reduce cell viability in NSCLC A549 cells, at least in part, through activation of the PKC-δ/PKD/ERK pathway, suggesting the potential of prostratin and GRC-2 as anticancer agents.
Highlights
Phorbol esters are naturally occurring diterpenoids isolated from plant species belonging to the Euphorbiaceae and Thymelaeaceae families [1]
The effects of GRC-2 and prostratin on the viability of A549 cancer cells were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay
The growth inhibitory effect of GRC-2 was observed in three other human cancer cell lines, H1299 non-small cell lung cancer (NSCLC) cells as well as MDA-MB-231 and MCF-7 breast cancer cells, to a lesser extent (Supplementary Figure S1)
Summary
Phorbol esters are naturally occurring diterpenoids isolated from plant species belonging to the Euphorbiaceae and Thymelaeaceae families [1]. Some phorbol derivatives exhibit potent anti-proliferation activity against cancer cells and are considered promising anticancer agents [2,5]. Phorbol esters act as potent and long-lasting DAG mimetics and can activate conventional and novel PKCs. PKCs play critical roles in regulating a variety of cellular responses, such as cell growth, differentiation, secretion, survival, and apoptosis [10]. Recent studies have shown that cancer-associated mutations in PKC are generally loss-of-function, suggesting the tumor-suppressor role for PKC [13]. These findings led to the hypothesis that restoring, rather than inhibiting, the activity of PKC may be a new strategy to combat cancer [14]. The relationships between PKD and phorbol esters have been less thoroughly investigated
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