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http://dx.doi.org/10.5352/JLS.2009.19.7.892

Cytotoxicity of Mifepristone via Calcium Modulation In Human Prostate Cancer Cells  

Song, Hwi-June (Department of Biological Sciences, Pusan National University)
Kim, Byeong-Gee (Department of Biological Sciences, Pusan National University)
Publication Information
Journal of Life Science / v.19, no.7, 2009 , pp. 892-898 More about this Journal
Abstract
MIF is a progesterone analogue and is known as a potent progesterone antagonist. Although MIF has been known to inhibit prostate cancer cell growth, its molecular mechanisms are not yet clear. In the present study, when the cells were treated for 2-4 days with 5-40 $\mu$M of MIF, the growth and viability of LNCaP cells were significantly decreased in a dose- and time-dependent manner. When the cells, cultivated in a normal 2 mM calcium concentration medium, were treated with 15 $\mu$M MIF for 1 day, the intracellular calcium level increased by 26% compared to the control. Similar results were also found in cells located in the calcium-free reaction buffer, indicating that MIF induced the increase of intracellular Ca$^{2+}$ levels, regardless of the presence of calcium in the surrounding medium. In the cells treated with various concentrations of MIF, the intracellular calcium levels increased in a dose dependent manner. Cells treated with MIF revealed typical early apoptotic signs, i.e., chromosome condensation and nuclei fragmentation. In cells treated with 40 11M MIF, Bcl-2 decreased to 19% of the control. The expression of Bax increased to almost 2 fold of the control. These results demonstrated very clearly that MIF treatment blocks the expression of Bcl-2 but stimulates the expression of Bax. According to the results of the present investigation, the apoptotic mechanism of MIF is triggered by intracellular modulation.
Keywords
Apoptosis; calcium signaling; mifepristone; prostate cancer;
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1 Smaili, S. S., Y.-T. Hsu, A. C. P. Carvalho, T. R. Rosenstock J. C. Sharpe, and R. J. Youle. 2003. Mitochondria, calcium and pro-apoptotic proteins as mediators in cell death signaling. Braz. J. Med. Biol. Res. 36, 183-190
2 Song, L.-N., M. Coghlan, and E. P. Gelmann. 2004. Antiandrogen effects of mifepristone on cocativator and corepressor interactions with the androgen receptor. Mol. Endocrinol. 18, 70-85   DOI   ScienceOn
3 Taplin, M.-E., J. Manola, W. K. Oh, P. W. Kantoff, G. L. Bubley, M. Smith, D. Barb, C. Mantzoros, D. P. Gelmann, and S. P. Balk. 2008. A phase II study of mifepristone (RU-486) in castration-resistnat prostate cancer, with a correlative assessment of androgen-related hormones. J. Compilation 101, 1084-1089
4 Wertz, I. E. and V. M. Dixit. 2000. Characterization of calcium release-activated apoptosis of LNCaP prostate cancer cells. J. Biol. Chem. 275, 11470-11477   DOI   ScienceOn
5 Zhang, H., J. J. Lu, Q. Z. Gao, and J. Zhang. 2006. Induction of apoptosis by mifepristone in androgen-independent prostate cancer cell lines in vitro. Zhonghua Wai Ke Za Zhi 44, 382-385
6 Zhang W., L. Huang, Y. Zhuang, and W. Wang. 2008. The effect of mifepristone on apoptosis and caspase-3 activation in human ovarian luteinized granulose cells. Eur. J. Obstet. Gynecol. Reprod. Biol. 141, 131-136   DOI   ScienceOn
7 Madsen-Bouterse, S. A., G. M. Rosa, and J. L. Bruton. 2006. Glucocorticoid modulation of Bcl-2 family members A1 and Bak during delayed spontaneous apoptosis of bovine blood neutrophils. Endocrinol. 147, 8826-8834
8 Moe, B. G., A. B. Vereide, A. Orbo, and G. Sager. 2009. High concentrations of progesterone and mifepristone mutually reinforce cell cycle retardation and induction of apoptosis. Anticancer Res. 29, 1053-1058
9 Nutt, L .K., J. Cahndra, A. Pataer, B. Fang, J. A. Roth, S. G. Swisher, R. G. O’neil, and D. J. McConkey. 2002. Bax-mediated Ca2+ mobilization promotes cytochrome c release during apoptosis. J. Biol. Chem. 277, 20301-20308   DOI   ScienceOn
10 Ozaki, M. A., H. Matsubara, T. Sato, K. Ikuta, Y. Nishizawa, and K. Suzumori. 2005. Role of apoptosis controlled by cytochrome c released from mitochondria for luteal function in human granulose cells. Am. J. Reprod. Immunol. 53, 144-152   DOI   ScienceOn
11 Pinton, P., D. Ferrari, E. Rapizzi, F. Di Virgilio, T. Pozzan, and R. Rizzuto. 2002. A role for calcium in bcl-2 action? 195-201 84, 195-201   DOI   ScienceOn
12 Schneider, C. C., R.K. Gibb, D. D. Taylor, T. Wan, and C. Gercel-Taylor. 1998. Inhibition of endometrial cancer cell lines by mifepristone (RU486). J. Soc. Gynecol. Investig. 5, 334-338   DOI   ScienceOn
13 Scorrano, L., S. A. Oakes, J. T. Opferman, D. H. Cheng, M. D. Scorcinelli, T. Pozzan, and S. J. Korsmeyer. 2003. Bax and bak regulation of endoplasmic reticulum $Ca^{2+}$: A control point for apoptosis. Science 300, 135-139   DOI   ScienceOn
14 Chami, M., A. Prandin, M. Campanella, P. Pinton, G. Szabadkai, J. C. Reed, and R. Rizzuto. 2004. Bcl-2 and bax exert opposing effects on $Ca^{2+}$ signaling, which do not depend on their putative pore-forming region. J. Biol. Chem. 279, 54581-54589   DOI   ScienceOn
15 Sharma, A. K. and B. Rohrer. 2004. Calcium-induced calpain mediates apoptosis via caspase-3 in a mouse photpreceptor cell line. 35564-35572. 279, 35564-35572   DOI   ScienceOn
16 Arraudeau, S., M. Frieden, K. Nakamura, C. Castelbou, M. Michalak, and N. Demaurex. 2002. Calreticulin differentially modulates calcium uptake and release in the endoplasmic reticulum and mitochondria. J. Biol. Chem. 277, 46696-46705   DOI   ScienceOn
17 Cabeza, M., E. Bratoeff, I. Heuze, A. Guzman, G. Gomez, H. Berrios, and A. M. Rosales. 2007. Antiandrogenic and apoptotic effects of RU-486 on animal prostate. J. Steroid Biochem. Mol. Biol. 104, 321-325   DOI   ScienceOn
18 Chaudhary, K. S., P. D. Abel, and E. -N. Lalani. 1999. Role of the Bcl-2 gene family in prostate cancer progression and its implications for therapeutic intervention. Environmnt. Health Perspect. 107, 49-57   DOI   ScienceOn
19 El Etreby, M. F., Y. Liang, and R. W. Lewis. 2000. Induction of apoptosis by mifepristone and tamoxifen in human LNCaP prostate cancer cells in culture. The Prostate 43, 31-42.   DOI   ScienceOn
20 Ferrari, D., P. Pinton, G. Szabadkai, M. Chami, M. Campanella, T. Pozzan, and R. Rizzuto. 2002. Endoplasmic reticulum, bcl-2 and $Ca^{2+}$ handling in apoptosis. Cell Calcium 32, 413-420   DOI   ScienceOn
21 Hajnoczly, G., E. Davies, and M. Muniswamy. 2003. Calcium signaling and apoptosis. Biochem. Biophys. Res. Commun. 304, 445-454   DOI   ScienceOn
22 Li, A., J. C. Felix, P. Minoo, C.A. Amezcua, and J. K. Jain. 2005. Effect of mifepristone on proliferation and apoptosis of ishikawa endometrial adenocarcinoma cells. Fertil. Steril. 84, 202-211   DOI   ScienceOn