title: Inhibition of the proteasome activity, a novel mechanism associated with the tumor cell apoptosis-inducing ability of genistein.
abstract: Epidemiological studies have suggested that increased soy consumption is associated with reduced cancer occurrence. Genistein, a soy isoflavone, has been reported to inhibit the growth of human tumor cells although the involved molecular mechanisms are not clearly defined. Here we report that genistein inhibits the proteasomal chymotrypsin-like activity in vitro and in vivo. Computational docking studies suggest that the interaction of genistein with the proteasomal beta 5 subunit is responsible for inhibition of the chymotrypsin-like activity. Inhibition of the proteasome by genistein in prostate cancer LNCaP and breast cancer MCF-7 cells is associated with accumulation of ubiquitinated proteins and three known proteasome target proteins, the cyclin-dependent kinase inhibitor p27(Kip1), inhibitor of nuclear factor-kappa B (I kappa B-alpha), and the pro-apoptotic protein Bax. Genistein-mediated proteasome inhibition was accompanied by induction of apoptosis in these solid tumor cells. Finally, genistein induced proteasome inhibition and apoptosis selectively in simian virus 40-transformed human fibroblasts, but not in their parental normal counterpart. Our results suggest that the proteasome is a potential target of genistein in human tumor cells and that inhibition of the proteasome activity by genistein might contribute to its cancer-preventive properties.
authors.affiliation: Drug Discovery Program, H. Lee Moffitt Cancer Center & Research Institute, Department of Interdisciplinary Oncology, College of Medicine, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Aslamuzzaman
authors.initials: A
authors.lastname: Kazi
authors.forename: Kenyon G
authors.initials: KG
authors.lastname: Daniel
authors.forename: David M
authors.initials: DM
authors.lastname: Smith
authors.forename: Nagi B
authors.initials: NB
authors.lastname: Kumar
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology; D002472:Cell Transformation, Viral / Q000187:drug effects; D002918:Chymotrypsin / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D008297:Male; D009097:Multienzyme Complexes / Q000187:drug effects* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology; D046988:Proteasome Endopeptidase Complex; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D007529:Isoflavones; D009097:Multienzyme Complexes; D016159:Tumor Suppressor Protein p53; D019833:Genistein; D002918:Chymotrypsin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex