MEK4 function, genistein treatment, and invasion of human prostate cancer cells

Li Xu, Yongzeng Ding, William J. Catalona, Ximing J. Yang, Wayne F. Anderson, Borko Jovanovic, Kenji Wellman, Jaqueline Killmer, Xiaoke Huang, Karl A. Scheidt, R. Bruce Montgomery, Raymond Bergan

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Background - Dietary intake of genistein by patients with prostate cancer has been associated with decreased metastasis and mortality. Genistein blocks activation of p38 mitogen-activated protein kinase and thus inhibits matrix metalloproteinase-2 (MMP-2) expression and cell invasion in cultured cells and inhibits metastasis of human prostate cancer cells in mice. We investigated the target for genistein in prostate cancer cells.MethodsProstate cell lines PC3-M, PC3, 1532NPTX, 1542NPTX, 1532CPTX, and 1542CPTX were used. All cell lines were transiently transfected with a constitutively active mitogen-activated protein kinase kinase 4 (MEK4) expression vector (to increase MEK4 expression), small interfering RNA against MEK4 (to decrease MEK4 expression), or corresponding control constructs. Cell invasion was assessed by a Boyden chamber assay. Gene expression was assessed by a quantitative reverse transcription-polymerase chain reaction. Protein expression was assessed by Western blot analysis. Modeller and AutoDock programs were used for modeling of the structure of MEK4 protein and ligand docking, respectively. MMP-2 transcript levels were assessed in normal prostate epithelial cells from 24 patients with prostate cancer from a phase II randomized trial comparing genistein treatment with no treatment. Statistical significance required a P value of. 050 or less. All statistical tests were two-sided.ResultsOverexpression of MEK4 increased MMP-2 expression and cell invasion in all six cell lines. Decreased MEK4 expression had the opposite effects. Modeling showed that genistein bound to the active site of MEK4. Genistein inhibited MEK4 kinase activity with a half maximal inhibitory concentration of 0.40 μM (95% confidence interval [CI] = 0.36 to 0.45 μM). The MMP-2 transcript level in normal prostate epithelial cells was statistically significantly higher in the untreated group (100%) than in the genistein-treated group (24%; difference = 76%, 95% CI = 38% to 115%; P =. 045).ConclusionsWe identified MEK4 as a proinvasion protein in six human prostate cancer cell lines and the target for genistein. We showed, to our knowledge for the first time, that genistein treatment, compared with no treatment, was associated with decreased levels of MMP-2 transcripts in normal prostate cells from prostate cancer-containing tissue.

Original languageEnglish (US)
Pages (from-to)1141-1155
Number of pages15
JournalJournal of the National Cancer Institute
Volume101
Issue number16
DOIs
StatePublished - Aug 2009
Externally publishedYes

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Genistein
Prostatic Neoplasms
Matrix Metalloproteinase 2
Prostate
Cell Line
Therapeutics
Epithelial Cells
MAP Kinase Kinase 4
Confidence Intervals
Neoplasm Metastasis
Proteins
p38 Mitogen-Activated Protein Kinases
Small Interfering RNA
Reverse Transcription
Cultured Cells
Catalytic Domain
Phosphotransferases
Western Blotting
Ligands
Gene Expression

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

MEK4 function, genistein treatment, and invasion of human prostate cancer cells. / Xu, Li; Ding, Yongzeng; Catalona, William J.; Yang, Ximing J.; Anderson, Wayne F.; Jovanovic, Borko; Wellman, Kenji; Killmer, Jaqueline; Huang, Xiaoke; Scheidt, Karl A.; Montgomery, R. Bruce; Bergan, Raymond.

In: Journal of the National Cancer Institute, Vol. 101, No. 16, 08.2009, p. 1141-1155.

Research output: Contribution to journalArticle

Xu, L, Ding, Y, Catalona, WJ, Yang, XJ, Anderson, WF, Jovanovic, B, Wellman, K, Killmer, J, Huang, X, Scheidt, KA, Montgomery, RB & Bergan, R 2009, 'MEK4 function, genistein treatment, and invasion of human prostate cancer cells', Journal of the National Cancer Institute, vol. 101, no. 16, pp. 1141-1155. https://doi.org/10.1093/jnci/djp227
Xu, Li ; Ding, Yongzeng ; Catalona, William J. ; Yang, Ximing J. ; Anderson, Wayne F. ; Jovanovic, Borko ; Wellman, Kenji ; Killmer, Jaqueline ; Huang, Xiaoke ; Scheidt, Karl A. ; Montgomery, R. Bruce ; Bergan, Raymond. / MEK4 function, genistein treatment, and invasion of human prostate cancer cells. In: Journal of the National Cancer Institute. 2009 ; Vol. 101, No. 16. pp. 1141-1155.
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title = "MEK4 function, genistein treatment, and invasion of human prostate cancer cells",
abstract = "Background - Dietary intake of genistein by patients with prostate cancer has been associated with decreased metastasis and mortality. Genistein blocks activation of p38 mitogen-activated protein kinase and thus inhibits matrix metalloproteinase-2 (MMP-2) expression and cell invasion in cultured cells and inhibits metastasis of human prostate cancer cells in mice. We investigated the target for genistein in prostate cancer cells.MethodsProstate cell lines PC3-M, PC3, 1532NPTX, 1542NPTX, 1532CPTX, and 1542CPTX were used. All cell lines were transiently transfected with a constitutively active mitogen-activated protein kinase kinase 4 (MEK4) expression vector (to increase MEK4 expression), small interfering RNA against MEK4 (to decrease MEK4 expression), or corresponding control constructs. Cell invasion was assessed by a Boyden chamber assay. Gene expression was assessed by a quantitative reverse transcription-polymerase chain reaction. Protein expression was assessed by Western blot analysis. Modeller and AutoDock programs were used for modeling of the structure of MEK4 protein and ligand docking, respectively. MMP-2 transcript levels were assessed in normal prostate epithelial cells from 24 patients with prostate cancer from a phase II randomized trial comparing genistein treatment with no treatment. Statistical significance required a P value of. 050 or less. All statistical tests were two-sided.ResultsOverexpression of MEK4 increased MMP-2 expression and cell invasion in all six cell lines. Decreased MEK4 expression had the opposite effects. Modeling showed that genistein bound to the active site of MEK4. Genistein inhibited MEK4 kinase activity with a half maximal inhibitory concentration of 0.40 μM (95{\%} confidence interval [CI] = 0.36 to 0.45 μM). The MMP-2 transcript level in normal prostate epithelial cells was statistically significantly higher in the untreated group (100{\%}) than in the genistein-treated group (24{\%}; difference = 76{\%}, 95{\%} CI = 38{\%} to 115{\%}; P =. 045).ConclusionsWe identified MEK4 as a proinvasion protein in six human prostate cancer cell lines and the target for genistein. We showed, to our knowledge for the first time, that genistein treatment, compared with no treatment, was associated with decreased levels of MMP-2 transcripts in normal prostate cells from prostate cancer-containing tissue.",
author = "Li Xu and Yongzeng Ding and Catalona, {William J.} and Yang, {Ximing J.} and Anderson, {Wayne F.} and Borko Jovanovic and Kenji Wellman and Jaqueline Killmer and Xiaoke Huang and Scheidt, {Karl A.} and Montgomery, {R. Bruce} and Raymond Bergan",
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T1 - MEK4 function, genistein treatment, and invasion of human prostate cancer cells

AU - Xu, Li

AU - Ding, Yongzeng

AU - Catalona, William J.

AU - Yang, Ximing J.

AU - Anderson, Wayne F.

AU - Jovanovic, Borko

AU - Wellman, Kenji

AU - Killmer, Jaqueline

AU - Huang, Xiaoke

AU - Scheidt, Karl A.

AU - Montgomery, R. Bruce

AU - Bergan, Raymond

PY - 2009/8

Y1 - 2009/8

N2 - Background - Dietary intake of genistein by patients with prostate cancer has been associated with decreased metastasis and mortality. Genistein blocks activation of p38 mitogen-activated protein kinase and thus inhibits matrix metalloproteinase-2 (MMP-2) expression and cell invasion in cultured cells and inhibits metastasis of human prostate cancer cells in mice. We investigated the target for genistein in prostate cancer cells.MethodsProstate cell lines PC3-M, PC3, 1532NPTX, 1542NPTX, 1532CPTX, and 1542CPTX were used. All cell lines were transiently transfected with a constitutively active mitogen-activated protein kinase kinase 4 (MEK4) expression vector (to increase MEK4 expression), small interfering RNA against MEK4 (to decrease MEK4 expression), or corresponding control constructs. Cell invasion was assessed by a Boyden chamber assay. Gene expression was assessed by a quantitative reverse transcription-polymerase chain reaction. Protein expression was assessed by Western blot analysis. Modeller and AutoDock programs were used for modeling of the structure of MEK4 protein and ligand docking, respectively. MMP-2 transcript levels were assessed in normal prostate epithelial cells from 24 patients with prostate cancer from a phase II randomized trial comparing genistein treatment with no treatment. Statistical significance required a P value of. 050 or less. All statistical tests were two-sided.ResultsOverexpression of MEK4 increased MMP-2 expression and cell invasion in all six cell lines. Decreased MEK4 expression had the opposite effects. Modeling showed that genistein bound to the active site of MEK4. Genistein inhibited MEK4 kinase activity with a half maximal inhibitory concentration of 0.40 μM (95% confidence interval [CI] = 0.36 to 0.45 μM). The MMP-2 transcript level in normal prostate epithelial cells was statistically significantly higher in the untreated group (100%) than in the genistein-treated group (24%; difference = 76%, 95% CI = 38% to 115%; P =. 045).ConclusionsWe identified MEK4 as a proinvasion protein in six human prostate cancer cell lines and the target for genistein. We showed, to our knowledge for the first time, that genistein treatment, compared with no treatment, was associated with decreased levels of MMP-2 transcripts in normal prostate cells from prostate cancer-containing tissue.

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