Genistein Inhibits p38 Map Kinase Activation, Matrix Metalloproteinase Type 2, and Cell Invasion in Human Prostate Epithelial Cells

Abstract

Epidemiologic studies associate consumption of genistein, in the form of dietary soy, with lower rates of metastatic prostate cancer. We have previously shown that genistein inhibits prostate cancer cell detachment in vitro, that it is well tolerated in an older cohort of men with prostate cancer, and that it alters cell signaling in that same cohort. We have also shown that p38 mitogen-activated protein kinase (MAPK) is necessary for transforming growth factor beta (TGF-beta)-mediated increases in prostate cancer adhesion. Although cell invasion is closely linked to metastatic behavior, little is known about how this process is regulated in prostate cancer or what effect, if any, genistein has on associated processes. We now show that genistein inhibits matrix metalloproteinase type 2 (MMP-2) activity in six of seven prostate cell lines tested, blocks MMP-2 induction by TGF-beta, and inhibits cell invasion. Efficacy was seen at low nanomolar concentrations, corresponding to blood concentrations of free genistein attained after dietary consumption. Inhibition of p38 MAPK by either SB203580 or dominant-negative construct blocked induction of MMP-2 and cell invasion by TGF-beta. Genistein exerted similar effects and was found to block activation of p38 MAPK by TGF-beta. This study shows that p38 MAPK is necessary for TGF-beta-mediated induction of MMP-2 and cell invasion in prostate cancer and that genistein blocks activation of p38 MAPK, thereby inhibiting processes closely linked to metastasis, and does so at concentrations associated with dietary consumption. Any potential causal link to epidemiologic findings will require further investigation.

TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial–mesenchymal transition

“…We found that depleting TMPRSS4 in cell lines established from lung and colon cancers using siRNA affected cell proliferation via regulation of cell cycle progression, invasion and adhesion in vitro, which may be a result of downregulation of ERK1/2 and p38 MAPK activation. p38 MAPK has been reported to be involved in various metastatic processes (Laferriere et al, 2002;Huang et al, 2005). It is intriguing to consider that TMPRSS4 may modulate the activation of MAPKs to contribute to a malignant phenotype of cancer cells.…”

Molecular effectors and modulators of hypericin-mediated cell death in bladder cancer cells

“…The pleiotropic p38 MAPK appears to contribute to carcinogenesis by regulating growth factor expression (Elenitoba-Johnson et al, 2003;Tsai et al, 2003;Lin et al, 2004), inflammatory- (Park et al, 2003), and invasion-associated genes, including members of the MMP family (Johansson et al, 2000;Reunanen et al, 2002;Suarez-Cuervo et al, 2004;Huang et al, 2005).…”

Endoglin inhibits prostate cancer motility via activation of the ALK2-Smad1 pathway

“…Compared to PC3-M cells, PC3 cells express higher levels of ENG (Liu et al, 2002), are less invasive (Huang et al, 2005), have a lower propensity to detach (Bergan et al, 1996b), are less metastatic (Kozlowski et al, 1984) and are B10-fold less sensitive to TGFb (as assessed by growth inhibition) .…”