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Enterolactone Induces Apoptosis in Human Prostate Carcinoma Lncap Cells Via a Mitochondrial-Mediated, Caspase-Dependent Pathway

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Enterolactone Induces Apoptosis in Human Prostate Carcinoma Lncap Cells Via a Mitochondrial-Mediated, Caspase-Dependent Pathway 2581 Enterolactone induces apoptosis in human prostate carcinoma LNCaP cells via a mitochondrial-mediated, caspase-dependent pathway Li-Hua Chen,1 Jing Fang,1 Huaixing Li,1 United States and China (1, 2). Diet is considered a primary Wendy Demark-Wahnefried,2 and Xu Lin1 factor contributing to the huge differential in the preva- lence of prostatic carcinoma (3). Although there are several 1 Institute for Nutritional Sciences, Shanghai Institutes for dietary factors that may be important for this disease, we Biological Sciences, Chinese Academy of Sciences, and Graduate School of the Chinese Academy of Sciences, Shanghai, China; propose a study that specifically focuses on dietary lignans and 2School of Nursing and Department of Surgery, Duke because the traditional plant-based diet in Asia is rich University Medical Center, Durham, North Carolina in lignans as compared with the omnivorous diet of the United States and Northern Europe (4). Moreover, our previous studies suggest an inhibitory effect of this Abstract phytochemical on prostate cancer growth (5). The mammalian lignan enterolactone is a major metabolite Dietary lignans have phytoestrogenic properties (6) and of plant-based lignans that has been shown to inhibit the are broadly available in cereals, legumes, fruits, vegetables, growth and development of prostate cancer. However, and grains, with the highest concentration in flaxseed and little is known about the mechanistic basis for its anti- sesame seeds (7, 8). Plant-based lignans, secoisolariciresinol cancer activity. In this study, we report that enterolactone and matairesinol, are converted by the intestinal microflora selectively suppresses the growth of LNCaP prostate to mammalian lignans of enterodiol and enterolactone, the cancer cells by triggering apoptosis. Mechanistic studies major forms in the biological fluids of humans and animals showed that enterolactone-induced apoptosis was char- (ref. 9; Fig. 1A). Enterolactone was reported to inhibit acterized by a dose-dependent loss of mitochondrial mem- mammary carcinogenesis in rats (10), and enterolactone, c brane potential, release of cytochrome and cleavage of enterodiol, and other mammalian lignan derivatives were procaspase-3 and poly(ADP-ribose)-polymerase (PARP). also found to suppress breast and colon cancer cell growth Caspase dependence was indicated by the ability of the pan- in vitro (11, 12). caspase inhibitor z-VAD-fmk to attenuate enterolactone- The association between enterolactone and prostate mediated apoptosis. Mechanistic studies suggested roles for cancer risk in epidemiologic studies is limited and remains B Akt, GSK-3 , MDM2, and p53 in enterolactone-dependent controversial. Kilkkinen et al. (13) reported the results from apoptosis. Our findings encourage further studies of enter- a nested case-control study, in which serum enterolactone olactone as a promising chemopreventive agent against levels were not significantly different between prostate prostate cancer. [Mol Cancer Ther 2007;6(9):2581–90] cancer patients and controls. In contrast, in a recent population-based study from Sweden, Hedelin et al. (14) Introduction found that serum levels of enterolactone were inversely Prostatic carcinoma is the second most frequently diagnosed associated with prostate cancer risk. However, due to the cancer worldwide and is one of the major life-threatening limited availability of purified lignans, only a few studies diseases among men (1). Although the incidence of latent have investigated the causal relationship between lignans prostate cancer is similar across all ethnic populations, and prostate cancer. Demark-Wahnefried et al. (15) there is an 80-fold difference in incidence and a 16-fold observed lower rates of proliferation and higher rates of difference in mortality of prostate cancer between the apoptosis in the tumors of patients following a flaxseed- supplemented, fat-modified diet before prostatectomy; they also found suppressed levels of total and free testosterone from baseline to follow-up. Reduced free Received 3/29/07; revised 6/7/07; accepted 7/18/07. androgen index was also reported by Dalais et al. (16) in Grant support: National Natural Science Foundation of China (Grant 30371209), the Innovation Direction Projects of the Chinese Academy patients treated with flaxseed and soy grits. Our previous of Sciences (KSCX2-2-25), Science and Technology Commission of animal study also showed that 5% flaxseed supplementa- Shanghai Municipality (Grant 04DZ14007), and the National Cancer Institute (R01 CA85740). tion significantly inhibited tumor burden and malignancy The costs of publication of this article were defrayed in part by the in male transgenic adenocarcinoma mouse prostate mice payment of page charges. This article must therefore be hereby marked (17). Moreover, our in vitro study also showed that advertisement in accordance with18 U.S.C. Section 1734 solely to enterodiol and enterolactone significantly decreased cell indicate this fact. viability in three human prostate cancer cell lines, and Requests for reprints: Xu Lin, Institute for Nutritional Sciences, 294 Tai Yuan Rd., Shanghai 200031, China. Phone: 86-21-5492-0249; enterolactone was more potent than enterodiol (5). More Fax: 86-21-5492-0291. E-mail: [email protected] recently, the plant lignan 7-hydroxymatairesinol, a precur- Copyright C 2007 American Association for Cancer Research. sor of enterolactone, was found to significantly reduce doi:10.1158/1535-7163.MCT-07-0220 tumor burden in mice with LNCaP xenografts (18). Mol Cancer Ther 2007;6(9). September 2007 Downloaded from mct.aacrjournals.org on October 1, 2021. © 2007 American Association for Cancer Research. 2582 Enterolactone Induces Apoptosis in Prostate Cancer Figure 1. Enterolactone decreases cell viability in human prostate carcinoma LNCaP cells but not in human nontumorigenic prostate epithelial cells. A, chemical structure of enterolactone. B, MTT assay on LNCaP cells. C, MTT assay on human nontumorigenic prostate epithelial CRL-2221 cells. D, trypan blue dye exclusion assay on LNCaP cells. Columns, mean of three independent experiments; bars, SE. Non-corresponding letters indicate significant differences at P < 0.05. Together, the evidence from in vivo and in vitro research Materials and Methods suggests anticancer activity of lignans in prostate cancer; Reagents however, the specific mechanisms are not yet well This study used JC-1 dye (5,5¶,6,6¶-tetrachloro-1,1¶,3,3¶-tetra- understood. In general, the modulation of cell proliferation ethylbenzimidazolylcarbocyanine iodide; Molecular Probes) and apoptosis have been highlighted as key players for the and the pan-caspase inhibitor, z-VAD-fmk (Promega). We also overall efficacy of anticancer agents (19). Lower prolifera- purchased antibodies from Cell Signaling [phospho-Akt tion rates and higher apoptotic indices have been observed (Ser473), Akt, phospho–GSK-3h and phospho-MDM2], Santa in both humans and animals treated with lignan-rich diets Cruz Biotechnology [p53, MDM2, caspase-3 (cleaved), and (15, 17, 18, 20, 21). Accumulating evidence suggests that glyceraldehyde-3-phosphate dehydrogenase (GAPDH)], and reduced cancer cell apoptosis is essential for the transition BD PharMingen [cleavage site-specific poly(ADP-ribose)- of prostatic carcinoma from latent to clinically overt and polymerase (PARP) and cytochrome c]. Enterolactone, 3-(4,5- from hormone-sensitive to hormone-insensitive disease dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (22, 23). Therefore, the objective of the present study was (MTT), trypan blue dye, and other chemicals that were not to thoroughly investigate enterolactone-induced apoptosis specifically indicated were purchased from Sigma. and explore potential mechanism(s) by which enterolactone Cell Culture and Treatment inhibits prostate cancer cell survival and stimulates The androgen-dependent human LNCaP prostate cancer apoptosis. cells and human nontumorigenic CRL-2221 prostate Mol Cancer Ther 2007;6(9). September 2007 Downloaded from mct.aacrjournals.org on October 1, 2021. © 2007 American Association for Cancer Research. Molecular Cancer Therapeutics 2583 epithelial cells were obtained from American Type Culture 100 Amol/L of enterolactone for 72 h. The floating and Collection. The normal human ovarian epithelial cell line trypsinized adherent cells were collected and washed IOSE80 and hepatocyte cell line HL-7702 (gifts from with PBS. The cell pellets were resuspended in 300 ALof Dr. Dong Xie, Institute for Nutritional Sciences, Shanghai, PBS and fixed by the addition of 700 AL of ice-cold China) and LNCaP cells were cultured in RPMI 1640 ethanol at À20jC. After incubation for 30 min, the cells supplemented with 10% fetal bovine serum (FBS), were re-pelleted by centrifugation and resuspended in 10 mmol/L HEPES, and 1% penicillin and streptomycin. 0.5 mL of PBS containing 100 Ag/mL of RNase and then CRL-2221 cells were cultured in keratinocyte-SFM media incubated at 37jC for 30 min. Finally, the cells were supplemented with epidermal growth factor (0.2 ng/mL), stained with 0.5 mL of PI solution (100 Ag/mL in PBS) bovine pituitary extract (30 Ag/mL), and 1% penicillin and for 30 min. Cell cycle distribution was detected by a streptomycin (all components were purchased from Life FACScalibur flow cytometer (Becton Dickinson), and data Technologies BRL). The cells were maintained at 37jC were analyzed using the ModFit LT for Mac V1.01 in a 5% CO2 humidified incubator. Enterolactone was software. Cells with sub–G0-G1
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