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http://dx.doi.org/10.5352/JLS.2006.16.4.589

Induction of G2/M Arrest of the Cell Cycle by Genistein in Human Bladder Carcinoma and Leukemic Cells  

Kim, Eu-Kyum (Korea Science Academy)
Myong, You-Ho (Korea Science Academy)
Song, Kwan-Sung (Korea Science Academy)
Lee, Ki-Hong (Korea Science Academy)
Rhu, Chung-Ho (Division of Applied Life Science, Gyeongsang National University)
Choi, Yung-Hyun (Department of Biochemistry, Dongeui University College of Oriental Medicine and Department of Biomaterial Control, Dongeui University Graduate School)
Publication Information
Journal of Life Science / v.16, no.4, 2006 , pp. 589-597 More about this Journal
Abstract
Genistein, a natural isoflavonoid phytoestrogen, is a strong inhibitor of protein tyrosine kinase and DNA topoisomerase activities. There are several studies documenting molecular alterations leading to cell cycle arrest and induction of apoptosis by genistein as a chemopreventive agent in a variety of cancer cell lines; however, its mechanism of action and its molecular targets on human bladder carcinoma and leukemic cells remain unclear. In the present study, we have addressed the mechanism of action by which genistein suppressed the proliferation of T24 bladder carcinoma and U937 leukemic cells. Genistein significantly inhibited the cell growth and induced morphological changes, and induced the G2/M arrest of the cell cycle in both T24 and U937 cells with a relatively stronger cytotoxicity in U937. The G2/M arrest in T24 cells was associated with the inhibition of cyclin A, cyclin B1 and Cdc25C protein expression without alteration of tumor suppressor p53 and cyclin-dependent kinase (Cdk) inhibitor p21(WAF1/CIP1). However, the inhibitory effects of genistein on the cell growth of U937 cells were connected with a marked inhibition of cyclin B1 and an induction of Cdk inhibitor p21 proteins by p53-independent manner. These data suggest that genistein may exert a strong anticancer effect and additional studies will be needed to evaluate the different mechanisms between T24 and U937 cells.
Keywords
Genistein; T24; U937; cell cycle; G2/M arrest;
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1 Guadagno, T.M., M. Ohtsubo, J.M. Roberts and R.K. Assoian. 1993. A link between cyclin A expression and adhesion-dependent cell cycle progression. Science 262, 1572-1575   DOI
2 Shao, Z.-M., M.L. Alpaugh, J.A. Fontana and S.H. Barsky. 1998. Genistein inhibits proliferation similarly in estrogen receptor-positive and negative human breast carcinoma cell lines characterized by $p21^{WAF1/CIP1}$ induction, G2/M arrest, and apoptosis. J. Cell. Biochem. 69, 44-54   DOI   ScienceOn
3 Bektic, J., R. Guggenberger, I.E. Eder, A.E. Pelzer, A.P. Berger, G. Bartsch and H. Klocker. 2005. Molecular effects of the isoflavonoid genistein in prostate cancer. Clin. Prostate Cancer 4, 124-129   DOI   ScienceOn
4 Datto, M.B., Y. Yu and X.-F. Wang. 1995. Functional analysis of the transforming growth factor ${\beta}$ responsive elements in the WAF/Cip1/p21 promoter. J. Biol. Chem. 270, 28623-28628   DOI
5 Mueller, S.C., Y. Yeh and W.T. Chen. 1992. Tyrosine phosphorylation of membrane proteins mediates cellular invasion by transformed cells. J. Cell Biol. 119, 1309-1325   DOI   ScienceOn
6 Xiong, Y., G. Hannon, H. Zhang, D. Casso, R. Kobayashi and D. Beach. 1993. p21 is a universal inhibitor of cyclin kinases. Nature 366,701-704   DOI   ScienceOn
7 Zhang, W., L. Grasso, C.D. McClain, A.M. Gambel, Y. Cha, S. Travali, A.B. Deisseroth and W.E. Mercer. 1995. p53-independent induction of WAF1/CIP1 in human leukemia cells is correlated with growth arrest accompanying monocyte/marcrophage differentiation. Cancer Res. 55, 668-674
8 Zi, X., D.K. Feyes and R. Agarwal. 1998. Anticarcinogenic effect of a flavonoid antioxidant, silymarin, in human breast canecr cells MDA-MB 468: induction of G1 arrest through an increase in Cip1/p21 concomitant with a decrease in kinase activity of cyclin-dependent kinase and associated cyclins. Clinical Cancer Res. 4, 1055-1064
9 Traganos, F., B. Ardelt, N. Halko, S. Bruno and Z. Darzynkiewicz. 1992. Effects of genistein on the growth and cell cycle progression of normal human lymphocytes and human leukemic MOLT-4 and HL-60 cells. Cancer Res. 52, 6200-6208
10 Mezencev, R., J. Mojzis, M. Pilatova and P. Kutschy. 2003. Antiproliferative and cancer chemopreventive activity of phytoalexins: focus on indole phytoalexins from crucifers. Neoplasma 50, 239-245
11 Ohtsubo, M. and J.M. Roberts. 1993. Cyclin-dependent regulation of G1 in mammalian fibroblasts. Science 259,1908-1912   DOI
12 Ravindranath, M.H., S. Muthugounder, N. Presser and S. Viswanathan. 2004. Anticancer therapeutic potential of soy isoflavone, genistein. Adv Exp Med Biol 546, 121-165   DOI
13 Sarkar, F.H. and Y. Li. 2002. Mechanisms of cancer chemoprevention by soy isoflavone genistein. Cancer Metastasis Rev 21, 265-280   DOI   ScienceOn
14 Spinozzi, F., C. Pagliacci, M. Graziella, M. Rasalba, F. Grignani, C. Riccardi and I. Nicoletti. 1994. The natural tyrosine kinase inhibitor genistein produces cell cycle arrest and apoptosis in jurkat T-leukemia cells. Leuk. Res. 18, 431-439   DOI   ScienceOn
15 Tchou, W.-W., W.N. Rom and K.-M. Tchou-Wong. 1996. Novel form of $p21^{WAF1/CIP1/SDI1}$ protein in phorbol ester-induced G2/M arrest. J. Biol. Chem. 271, 29556-29560   DOI   ScienceOn
16 Morgan, D.O. 1995. Principles of CDK regulation. Nature 374, 131-134   DOI   ScienceOn
17 Ohsumi, K., C. Katagiri and T. Kishimoto. 1993. Chromosome condensation in Xenopus mitotic extracts without histone H1. Science 262, 2033-2035   DOI
18 Santibanez, J.F., A. Navapro and J. Martinez. 1997. Genistein inhibits proliferation and in vitro invasive potential of human prostate cancer cell lines. Anticancer Res. 17,1199-1204
19 Li, Y., C.W. Jenkins, M.A. Nichols and Y. Xiong. 1994. Cell cycle expression and p53 regulation of the cyclin-dependent kinase p21. Oncogene 9, 2261-2268
20 Steele, V.E., M.A. Pereira, C.C. Sigman and G.J. Kelloff. 1995. Cancer chemoprevention agent development strategies for genistein. J. Nutri. 125, 713S-716S
21 Waga, S., G.J. Hannon, D. Beach and B. Stillman. 1994. The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature 369, 574-578   DOI   ScienceOn
22 Fattaey, A. and R.N. Booher. 1997. Myt1: a Wee1-type kinase that phosphorylates Cdc2 on residue Thr14. Prog. Cell Cycle Res. 3, 233-240
23 Fotsis, T., M. Pepper, H. Adlercreutz, G. Fleishmann, T. Hase, R. Montesano and L. Schweigerer. 1993. Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proc. Natl. Acad. Sci. USA 90, 2690-2694
24 Jiang, H., J. Lin, Z.Z. Su, F.R. Collart, E. Huberman and P.B. Fisher. 1994. Induction of differentiation in human promyelocytic HL-60 leukemia cells activates p21, WAF/CIP1, expression in the absence of p53. Oncogene 9, 3397-3406
25 Koff, A., A. Giordano, D. Desai, K. Yamashita, J.W. Harper, S. Elledge, T. Nishimoto, D.O. Morgan, B.R. Franza and J.M. Roberts. 1992. Formation and activation of a cyclin E-Cdk2 complex during the G1 phase of the human cell cycle. Science 257, 1689-1694   DOI
26 Krek, W. and E.A. Nigg. 1991. Differential phosphorylation of vertebrate $p34^{Cdc2}$ kinase at the G1/S and G2/M transitions of the cell cycle: identification of major phosphorylation sites. EMBO J. 10, 305-316
27 Markovits, J., C. Linassier, P.H. Fosse, J. Couprie, A. Jacquemin-Cablon, J.M. Saucier, J.B. Le Pecq and A. Larsen. 1989. Inhibitory effects of the tyrosine kinase inhibitor genistein on mammalian DNA topoisomerase. Cancer Res. 49, 5111-5117
28 Meyerson, M. and E. Harlow. 1994. Identification of G1 kinase activity for Cdk6, a novel cyclin D partner. Mol. Cell. Biol. 14, 2077-2086   DOI
29 Matsushime, H., D.E. Quelle, S.A. Shurtleff, M. Shibuya, C.J. Sherr and J.Y. Kato. 1994. D-type cyclin-dependent kinase activity in mammalian cells. Mol. Cell. Biol. 14, 2066-2076   DOI
30 Messina, M.J., V. Persky, K.D. Setchell and S. Barnes. 1994. Soy intake and cancer risk: a review of the in vitro and in vivo data. Nutr. Cancer 21, 113-131   DOI   ScienceOn
31 Belenguer, P., L. Pelloquin, V. Baldin, M.L. Oustrin and B. Ducommun. 1995. The fission yeast Nim1/Cdr1 kinase: a link between nutritional state and cell cycle control. Prog. Cell Cycle Res. 1, 207-214
32 Biggs, J.R., J.E. Kudlow and A.S. Kraft. 1995. The role of the transcription factor Sp1 in regulating the expression of the WAF1/CIP1 gene in U937 leukemic cells. J. Biol. Chem. 271, 901-906   DOI
33 Choi, Y.H., W.H. Lee, K.Y. Park and L. Zhang. 2000. p53-independent induction of p21 (WAF1/CIP1), reduction of cyclin B1 and G2/M arrest by the isoflavone genistein in human prostate carcinoma cells. Jpn. J. Cancer Res. 91, 164-173   DOI
34 Choi, Y.H., L. Zhang, W.H. Lee and K.Y. Park. 1998. Genistein-induced G2/M arrest is associated with the inhibition of cyclin B1 and the induction of p21 in human breast carcinoma cells. Int. J. Oncol. 13, 391-396
35 Constantinou, A., K. Kiguchi and E. Huberman. 1990. Induction of differentiation and DNA strand breakage in human HL-60 and K-562 leukemia cells by genistein. Cancer Res. 50, 2618-2624
36 Cooper, M.J., J.J. Haluschak, D. Johnson, S. Schwartz, L.J. Morrison, M. Lippa, G. Hatzivassiliou and J. Tan. 1994. p53 mutations in bladder carcinoma cell lines. Oncol. Res. 6, 569-579
37 Elledge, S.J. and J.W. Harper. 1994. Cdk inhibitors: on the threshold of checkpoints and development. Curr. Opin. Cell Biol. 6, 847-852   DOI   ScienceOn
38 Rauth, S., J. Kichina and A. Green. 1997. Inhibition of growth and induction of differentiation of metastatic melanoma cells in vitro by genistein: chemosensitivity is regulated by cellular p53. Bri. J. Cancer 75, 1559-1566   DOI   ScienceOn
39 Dorai, T. and B.B. Aggarwal. 2004. Role of chemopreventive agents in cancer therapy. Cancer Lett. 215, 129-140   DOI   ScienceOn
40 Dulic, V., G.H. Stein, D.F. Far and S.I. Reed. 1998. Nuclear accumulation of $p21^{Cip1}$ at the onset of mitosis: a role at the G2/M-phase transition. Mol. Cell. Biol. 18, 546-557   DOI
41 Sanchez, V., A.K. McElroy and D.H. Spector. 2003. Mechanisms governing maintenance of Cdk1/cyclin B1 kinase activity in cells infected with human cytomegalovirus. J. Virol. 77, 13214-13224   DOI
42 Kumagai, A. and W.G. Dunphy. 1991. The cdc25 protein controls tyrosine dephosphorylation of the cdc2 protein in a cell-free system. Cell 64, 903-914   DOI   ScienceOn
43 Akiyama, T., J. Ishida, S. Nakagawa, H. Ogawara, S. Watanabe, N. Itoh, M. Shibuya and Y. Fukami. 1987. Genistein, a specific inhibitor of tyrosine-specific protein kinase. J. Biol. Chem. 262, 5592-5595
44 Girard, F., U. Strausfeld, A. Fernandez and N.J.C. Lamb. 1991. Cyclin A is required for the onset of DNA replication in mammalian fibloblasts. Cell 67, 1169-1179   DOI   ScienceOn