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

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.