Genistein induces Gadd45 gene and G2/M cell cycle arrest in the DU145 human prostate cancer cell line

Division of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kioto, Kyōto, Japan
FEBS Letters (Impact Factor: 3.17). 12/2004; 577(1-2):55-9. DOI: 10.1016/j.febslet.2004.09.085
Source: PubMed


Genistein is the most abundant isoflavone of soybeans and has been shown to cause growth arrest in various human cancer cell lines. However, the precise mechanism for this is still unclear. We report here that the growth arrest and DNA damage-inducible gene 45 (gadd45) gene is induced by genistein via its promoter in a DU145 human prostate cancer cell line. The binding of transcription factor nuclear factor-Y to the CCAAT site of the gadd45 promoter appears to be important for this activation by genistein.

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    • "It has multiple facets of oncogenic signaling and is considered a promising agent for the protection of estrogen enhanced cancers (4). Genistein is a soy-derived isoflavone with multiple biochemical effects, including the cell cycle regulatory kinase activities (5, 6). It is believed to be a potent anticancer agent and found to inhibit tyrosine protein kinase (7). "
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    ABSTRACT: Induction of apoptosis in target cells is a key mechanism by which chemotherapy promotes cell killing. The purpose of this study was to determine whether Indole-3-Carbinol (I3C) and Genistein in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induce apoptosis in endometrial cancer cell (Ishikawa) and to assess apoptotic mechanism. The MTT assay and flow cytometry were performed to determine cell viability and cell cycle. The induction of apoptosis was measured by caspase-3 activity test, DNA fragmentation assay, annexin V binding assay and western blot analysis. There was no effect in cell growth inhibition and cell cycle progression alone or in two-combination. However, the treatment of I3C and Genistein followed by TRAIL showed significant cell death and marked increase in sub-G1 arrest. Three-combination treatment revealed elevated expression of DR4, DR5 and cleaved forms of caspase-3, caspase-8, PARP. The Flip was found down regulated. Moreover, increase in caspase-3 activity and DNA fragmentation indicated the induction of apoptosis. The results indicate that I3C and Genistein with TRAIL synergistically induced apoptosis via death receptor dependent pathway. Our findings might provide a new insight into the development of novel combination therapies against endometrial cancer.
    Journal of Korean medical science 04/2013; 28(4):527-33. DOI:10.3346/jkms.2013.28.4.527 · 1.27 Impact Factor
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    • "Genistein is a soy-derived isoflavone with multiple biochemical effects, including the alteration of cell cycle-regulatory kinase activities [4,5]. Previous studies indicated that genistein induced apoptosis, enhanced the induction of apoptosis by chemotherapeutic agents, and increased radiosensitivity in several cancer cell lines [4,6]. "
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    ABSTRACT: The chemopreventive effects of dietary phytochemicals on malignant tumors have been studied extensively because of a relative lack of toxicity. To achieve desirable effects, however, treatment with a single agent mostly requires high doses. Therefore, studies on effective combinations of phytochemicals at relatively low concentrations might contribute to chemopreventive strategies. Here we found for the first time that co-treatment with I3C and genistein, derived from cruciferous vegetables and soy, respectively, synergistically suppressed the viability of human colon cancer HT-29 cells at concentrations at which each agent alone was ineffective. The suppression of cell viability was due to the induction of a caspase-dependent apoptosis. Moreover, the combination effectively inhibited phosphorylation of Akt followed by dephosphorylation of caspase-9 or down-regulation of XIAP and survivin, which contribute to the induction of apoptosis. In addition, the co-treatment also enhanced the induction of autophagy mediated by the dephosphorylation of mTOR, one of the downstream targets of Akt, whereas the maturation of autophagosomes was inhibited. These results give rise to the possibility that co-treatment with I3C and genistein induces apoptosis through the simultaneous inhibition of Akt activity and progression of the autophagic process. This possibility was examined using inhibitors of Akt combined with inhibitors of autophagy. The combination effectively induced apoptosis, whereas the Akt inhibitor alone did not. Although in vivo study is further required to evaluate physiological efficacies and toxicity of the combination treatment, our findings might provide a new insight into the development of novel combination therapies/chemoprevention against malignant tumors using dietary phytochemicals.
    Molecular Cancer 11/2009; 8(1):100. DOI:10.1186/1476-4598-8-100 · 4.26 Impact Factor
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    • "Genistein contributes to apoptosis and inhibits proliferation via promotion of antioxidant enzyme activities in prostate cancer cells of LNCaP and PC-3 [2], as well as DU-145 [3]. Genistein may also modulate correlative gene expression to promote cancer cell apoptosis through the influence of growth arrest and DNA damage-inducible gene 45 (Gad45) in DU-145 [4]. The mechanism of action of genistein is complex and includes several cellular pathways . "
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    ABSTRACT: To further investigate the effect of a combination of genistein with survivin of RNA interference on the proliferation and apoptosis of DU-145 cells, the effect of genistein on the proliferation of DU-145 cells was detected by the MTT method and cytometry, and the apoptosis of cells was observed with fluorescence microscopy. In order to test combined genistein with transfection of small interfering RNA (siRNA) against survivin, a survivin siRNA plasmid was constructed and transfected into DU-145 cells. Genistein inhibited proliferation and induced apoptosis of cancerous DU-145 and Hela cells, whereas genistein had minimal effects for normal L-O2 cells. The stable transfected cell lines of DU-145, knockdown survivin by siRNA, displayed stronger apoptotic than untransfected DU-145, the transfected cell of DU-145 treated with genistein demonstrated the inhibition of proliferation and induction of apoptosis significantly; it showed genistein synergistic effect with RNAi in survivin for inhibition of prostate cancer cells.
    Cancer letters 06/2009; 284(2):189-97. DOI:10.1016/j.canlet.2009.04.024 · 5.62 Impact Factor
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