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

Abstract

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.

• Authors: Russell Z Szmulewitz, Robert Clark, Tamara Lotan, Kristen Otto, Jennifer Taylor Veneris, Kay Macleod, Carrie Rinker-Schaeffer
• Journal: International journal of cancer (Int J Cancer) Vol. 130 Issue 3 Pg. 509-20 (Feb 01 2012) ISSN: 1097-0215 [Electronic] United States
• PMID: 21351092 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2011 UICC.

Chemical References

• MAP Kinase Kinase 4

Topics

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