Abstract
The present study aims to evaluate the anticancer effect of L-securinine on androgen-independent prostate cancer (AIPC) DU145 cells. L-securinine (2.5, 5, and 10 μM) treatment for 24, 48 and 72 h displayed strong growth inhibitory effect on DU145 cells in a concentration and time-dependent fashion but has less toxicity toward normal androgen-dependent LNCaP cells. Hoechst 332582 staining of DU145 cells and Annexin V-FITC/ PI dual-labeling followed by flow cytometry assay identified that this growth inhibition by L-securinine would be due to the induction of apoptosis. Moreover Transwell assay revealed that L-securinine significantly inhibited the cell migration/invasion ability of DU145 cells. Furthermore, results of western blotting showed that the involvement of mitochondrial apoptotic pathway in the L-securinine-induced apoptosis of DU145 cell, as evidenced by an increase in the protein expression of Bax, cleaved caspase-9, cleaved caspase-3, cytosolic cytochrome c, and cleaved PARP, together with a unchanged cleaved caspase-8 and decreased Bcl-2 protein expression. Also, L-securinine-induced antimetastatic activity in DU145 cells was associated with decreased protein expression of MMP-2 and MMP-9 and concurrent reduction of VEGF. In addition, further studies revealed that L-securinine may inhibit the protein expression of AGTR1, p-MEK1/2, p-ERK1/2, p-STAT3, PAX2, and p-PAX2, while the expression of ERK1/2, MEK1/2, and STAT3 protein retains intact. These findings suggest that L-securinine may be a promising chemopreventive agent against AIPC.
Highlights
Prostate cancer continues to be one of the most prevalent malignancies, and is the second leading cause of death amongst older men in western countries such as Europe and the United States [1], while its incidence is low in Asian countries
Androgen-independent DU145 cell line and androgen-dependent LNCaP cell line were purchased from the Cell Bank of Type Culture Collection of Chinese Academy of Sciences (Shanghai, China), and were cultured in DMEM supplemented with 10% heat–inactivated fetal bovine serum (FBS), penicillin (10 U/ml) and streptomycin (10 μg/ml), in a humidified incubator (Sanyo XD–101; Sanyo Electric Co., Ltd., Osaka, Japan) with 5% CO2 at 37◦C
No significant inhibitory effect of can be observed in androgen-dependent LNCaP cells after 24 and 48 h exposure of L-securinine at any concentrations (P>0.05), and only a significant inhibitory effect occurred at the high concentration of L-securinine (10 μM) after 72 h treatment compared with the control cells (P
Summary
Prostate cancer continues to be one of the most prevalent malignancies, and is the second leading cause of death amongst older men in western countries such as Europe and the United States [1], while its incidence is low in Asian countries. Molecular mechanisms underlying onset and progression of prostate cancer are not clear, there is a growing recognition amongst physicians that the cause of this frequently occurring disease arose mainly from a shift toward western diets and lifestyles. Another is considered to be altered gene expression in patients due to environmental factors [3]. Despite wide pharmacological properties associated with L-securinine, little information, if any is available in term of the antitumor effect of L-securinine on human prostate cancer cells and the underlying molecular mechanisms remain poorly understood. The present study was designed to investigate the effects of L-securinine on the growth and metastasis of androgen-dependent or independent prostate cancer cells and to explore the possible mechanisms of action
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