title: Genistein inhibits matrix metalloproteinase type 2 activation and prostate cancer cell invasion by blocking the transforming growth factor beta-mediated activation of mitogen-activated protein kinase-activated protein kinase 2-27-kDa heat shock protein pathway.
abstract: Genistein is a candidate cancer chemopreventive drug being tested in clinical trials. We have shown that genistein blocks prostate cancer (PCa) cell invasion, that p38 mitogen-activated protein (MAP) kinase regulates activation of matrix metalloproteinase type 2 (MMP-2) and cell invasion, and that genistein prevents transforming growth factor beta (TGFbeta) from activating p38 MAP kinase. More recently, we identified MAP kinase-activated protein kinase 2 (MAPKAPK2) and the 27-kDa heat shock protein (HSP27) as downstream regulators of p38 MAP kinase. However, MAPKAPK2 and HSP27 can be regulated by factors other than p38 MAP kinase, and HSP27 is up-regulated during PCa progression. The current study was undertaken to examine the role of MAPKAPK2 and HSP27 in modulating genistein-mediated regulation of PCa cell invasion. Genistein inhibited TGFbeta-mediated phosphorylation of MAPKAPK2 and HSP27. Inhibitory effects by genistein upon cell signaling, inhibition of MMP-2, and inhibition of invasion were retained when both PC3 and PC3-M cells were transfected with either wild-type MAPKAPK2 or HSP27. However, transfection with dominant-negative MAPKAPK2 or nonphosphorylatable mutant HSP27 led to decreases in cell invasion and to abrogation of responsiveness to either TGFbeta-mediated increases or genistein-mediated decreases in MMP-2 and cell invasion. It is noteworthy that, after transfection with constitutive active MAPKAPK2 or with pseudophosphorylated HSP27, levels of MMP-2 activation and cell invasion were high and overcame any inhibitory effect of genistein. These findings demonstrate that genistein-mediated inhibition of cell invasion rests upon blocking activation of the MAPKAPK2-HSP27 pathway, and that its activation during cancer progression has the potential to mitigate therapeutic efficacy.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Northwestern University Medical School, Robert H Laurie Cancer Center, Olson 8321, 240 East Huron St., Chicago, IL 60611-3008, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Bergan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology*; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D018832:Molecular Chaperones; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000970:Antineoplastic Agents; D019833:Genistein; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020778:Matrix Metalloproteinase 2; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D016212:Transforming Growth Factor beta; D000099190:MAP-Kinase-Activated Kinase 2; C057725:HSPB1 protein, human