MKK4 suppresses metastatic colonization by multiple highly metastatic prostate cancer cell lines through a transient impairment in cell cycle progression

Int J Cancer. 2012 Feb 1;130(3):509-20. doi: 10.1002/ijc.26005. Epub 2011 Apr 25.


Metastatic dissemination in prostate cancer is often early, but not all cancer cells form clinical metastases. Map kinase kinase 4 (MKK4) suppresses metastasis in a preclinical prostate cancer model. We hypothesize that MKK4 will specifically inhibit metastatic colonization through impaired proliferation. Three highly metastatic rat prostate cancer cell lines (AT6.1, Mat-Lu and AT3.1) were employed. Stably over-expressing HA-MKK4 or vector control lines were injected into immunocompromised mice. These experiments validated that HA-MKK4 specifically affects metastatic colonization and increases survival. Median survival (days) with HA-MKK4 vs. vector was 42 vs. 28 (p < 0.0001) for AT6.1, 25 vs. 19 (p < 0.0001) for Mat-Lu and 27 vs. 20 (p < 0.0001) for AT3.1. HA-MKK4 suppresses colonization within 14 days post dissemination, after which exponential proliferation resumes. Although overt metastases retain HA-MKK4, it is inactive within these lesions. Nonetheless, metastasis-derived cell lines were shown to retain functional HA-MKK4 and like their parental HA-MKK4 line are suppressed for experimental metastasis formation in vivo. Disseminated AT6.1-HA-MKK4 cells were analyzed and were found to have an alteration in cell cycle. Specifically, there was an accumulation of cells in G1-phase (p = 0.024) and decrease in S-phase (p = 0.037) compared with vector. In multiple prostate cancer lines, HA-MKK4 suppresses an early step in metastatic colonization. These data support a model in which MKK4 activation at the metastatic site causes a cell-cycle arrest, which is eventually overcome despite presence of functional HA-MKK4. Further studies will specifically interrogate the regulation of MKK4 activation within the metastatic microenvironment and the down-stream molecular events critical for metastasis suppression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Cycle Checkpoints* / genetics
  • Cell Line, Tumor
  • Cell Proliferation
  • G1 Phase / genetics
  • Gene Expression Regulation, Neoplastic
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / genetics
  • Lung Neoplasms / secondary
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism*
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis
  • Prostatic Neoplasms / enzymology*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology*
  • Rats
  • Tumor Burden / genetics


  • MAP Kinase Kinase 4