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Molecular pathway for (-)-epigallocatechin-3-gallate-induced cell cycle arrest and apoptosis of human prostate carcinoma cells.

Abstract

Epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent present in green tea, is a promising chemopreventive agent. We recently showed that green tea polyphenols exert remarkable preventive effects against prostate cancer in a mouse model and many of these effects are mediated by the ability of polyphenols to induce apoptosis in cancer cells [Proc. Natl. Acad. Sci. USA 98 (2001) 10350]. Earlier, we showed that EGCG causes a G0/G1 phase cell cycle arrest and apoptosis of both androgen-sensitive LNCaP and androgen-insensitive DU145 human prostate carcinoma cells, irrespective of p53 status [Toxicol. Appl. Pharmacol. 164 (2000) 82]. Here, we provide molecular understanding of this effect. We tested a hypothesis that EGCG-mediated cell cycle dysregulation and apoptosis is mediated via modulation of cyclin kinase inhibitor (cki)-cyclin-cyclin-dependent kinase (cdk) machinery. As shown by immunoblot analysis, EGCG treatment of LNCaP and DU145 cells resulted in significant dose- and time-dependent (i) upregulation of the protein expression of WAF1/p21, KIP1/p27, INK4a/p16, and INK4c/p18, (ii) down-modulation of the protein expression of cyclin D1, cyclin E, cdk2, cdk4, and cdk6, but not of cyclin D2, (iii) increase in the binding of cyclin D1 toward WAF1/p21 and KIP1/p27, and (iv) decrease in the binding of cyclin E toward cdk2. Taken together, our results suggest that EGCG causes an induction of G1 phase ckis, which inhibits the cyclin-cdk complexes operative in the G0/G1 phase of the cell cycle, thereby causing an arrest, which may be an irreversible process ultimately leading to apoptotic cell death. This is the first systematic study showing the involvement of each component of cdk inhibitor-cyclin-cdk machinery during cell cycle arrest and apoptosis of human prostate carcinoma cells by EGCG.

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  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Department of Urology, Jim & Eillen Dicke Research Laboratory, Case Western Reserve University, The Research Institute of University Hospitals of Cleveland, Cleveland, OH 44106, USA.

    ,

    Source

    Archives of biochemistry and biophysics 410:1 2003 Feb 01 pg 177-85

    MeSH

    Antineoplastic Agents, Phytogenic
    Apoptosis
    Carcinoma
    Carrier Proteins
    Catechin
    Cell Cycle
    Cell Cycle Proteins
    Cyclin-Dependent Kinase Inhibitor p16
    Cyclin-Dependent Kinase Inhibitor p18
    Cyclin-Dependent Kinase Inhibitor p21
    Cyclin-Dependent Kinase Inhibitor p27
    Cyclin-Dependent Kinases
    Cyclins
    Dose-Response Relationship, Drug
    Enzyme Inhibitors
    G1 Phase
    Humans
    Intracellular Signaling Peptides and Proteins
    Male
    Prostatic Neoplasms
    Signal Transduction
    Tumor Suppressor Proteins

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't
    Research Support, U.S. Gov't, Non-P.H.S.
    Research Support, U.S. Gov't, P.H.S.

    Language

    eng

    PubMed ID

    12559991

    Citation

    Gupta, Sanjay, et al. "Molecular Pathway for (-)-epigallocatechin-3-gallate-induced Cell Cycle Arrest and Apoptosis of Human Prostate Carcinoma Cells." Archives of Biochemistry and Biophysics, vol. 410, no. 1, 2003, pp. 177-85.
    Gupta S, Hussain T, Mukhtar H. Molecular pathway for (-)-epigallocatechin-3-gallate-induced cell cycle arrest and apoptosis of human prostate carcinoma cells. Arch Biochem Biophys. 2003;410(1):177-85.
    Gupta, S., Hussain, T., & Mukhtar, H. (2003). Molecular pathway for (-)-epigallocatechin-3-gallate-induced cell cycle arrest and apoptosis of human prostate carcinoma cells. Archives of Biochemistry and Biophysics, 410(1), pp. 177-85.
    Gupta S, Hussain T, Mukhtar H. Molecular Pathway for (-)-epigallocatechin-3-gallate-induced Cell Cycle Arrest and Apoptosis of Human Prostate Carcinoma Cells. Arch Biochem Biophys. 2003 Feb 1;410(1):177-85. PubMed PMID: 12559991.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Molecular pathway for (-)-epigallocatechin-3-gallate-induced cell cycle arrest and apoptosis of human prostate carcinoma cells. AU - Gupta,Sanjay, AU - Hussain,Tajamul, AU - Mukhtar,Hasan, PY - 2003/2/1/pubmed PY - 2003/2/22/medline PY - 2003/2/1/entrez SP - 177 EP - 85 JF - Archives of biochemistry and biophysics JO - Arch. Biochem. Biophys. VL - 410 IS - 1 N2 - Epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent present in green tea, is a promising chemopreventive agent. We recently showed that green tea polyphenols exert remarkable preventive effects against prostate cancer in a mouse model and many of these effects are mediated by the ability of polyphenols to induce apoptosis in cancer cells [Proc. Natl. Acad. Sci. USA 98 (2001) 10350]. Earlier, we showed that EGCG causes a G0/G1 phase cell cycle arrest and apoptosis of both androgen-sensitive LNCaP and androgen-insensitive DU145 human prostate carcinoma cells, irrespective of p53 status [Toxicol. Appl. Pharmacol. 164 (2000) 82]. Here, we provide molecular understanding of this effect. We tested a hypothesis that EGCG-mediated cell cycle dysregulation and apoptosis is mediated via modulation of cyclin kinase inhibitor (cki)-cyclin-cyclin-dependent kinase (cdk) machinery. As shown by immunoblot analysis, EGCG treatment of LNCaP and DU145 cells resulted in significant dose- and time-dependent (i) upregulation of the protein expression of WAF1/p21, KIP1/p27, INK4a/p16, and INK4c/p18, (ii) down-modulation of the protein expression of cyclin D1, cyclin E, cdk2, cdk4, and cdk6, but not of cyclin D2, (iii) increase in the binding of cyclin D1 toward WAF1/p21 and KIP1/p27, and (iv) decrease in the binding of cyclin E toward cdk2. Taken together, our results suggest that EGCG causes an induction of G1 phase ckis, which inhibits the cyclin-cdk complexes operative in the G0/G1 phase of the cell cycle, thereby causing an arrest, which may be an irreversible process ultimately leading to apoptotic cell death. This is the first systematic study showing the involvement of each component of cdk inhibitor-cyclin-cdk machinery during cell cycle arrest and apoptosis of human prostate carcinoma cells by EGCG. SN - 0003-9861 UR - https://www.unboundmedicine.com/medline/citation/12559991/Molecular_pathway_for_____epigallocatechin_3_gallate_induced_cell_cycle_arrest_and_apoptosis_of_human_prostate_carcinoma_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0003986102006689 DB - PRIME DP - Unbound Medicine ER -