Abstract 1407: Mitogen-activated protein kinase kinase 4 (MEK4) is a key regulator of prostate cancer progression

Abstract

Abstract Mitogen-activated protein kinase kinase 4 (MEK4) is a dual-specificity kinase that has been implicated in cancer progression in multiple cancer types, including prostate cancer (PCa). MEK4 is upregulated in invasive PCa lesions in human tissue. We hypothesize that increased MEK4 promotes PCa invasion and metastasis. Our group has created PC3-M cells stably transfected with either constitutively-active or increased levels of wild-type MEK4. In a Matrigel Boyden chamber assay, constitutively-active or wild-type MEK4 was shown to increase PCa invasion. Cancer cell invasion requires the coupling of cell migration with increased production of proteases. We hypothesized that MEK4 promoted invasion via production of proteases, but not via cell migration. Using an uncoated boyden chamber, MEK4 was shown not to affect migration. Using quantitative real time polymerase chain reaction (qRT/PCR), we went on to demonstrate that MEK4 increased MMP-2 and MMP-9 transcript expression, but did not affect MMP-10 expression. In addition to these studies, we have also looked at the effect of increased or constitutively-active MEK4 on an orthotopic mouse model of PCa. In this model, PCa cells are injected into the prostates of nude mice and tumor size, circulating tumor cells, and lung metastasis are quantified. Preliminary data shows that constitutively-active MEK4 causes an increase in primary tumor size as well as an increase in circulating tumor cells in both the blood and the bone marrow. In summary, we demonstrated that chronic high expression of MEK4 increases human PCa invasion, that this is not due to increased migration, but is associated with increases in MMP-2 and MMP-9. Further, constitutively-active MEK4 appears to have different biological effects than high levels of wild type MEK4 in vivo. Ongoing studies are evaluating the effect of wild type MEK4 and of constitutively-active MEK4 on the formation of distant soft tissue metastasis in the above murine model. In related studies we are seeking to identify downstream proteins critical for MEK4's effects on cell invasion and metastasis both in vitro and in vivo. We are also seeking to examine the effects of sustained MEK4 knockdown on PCa invasion and metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1407. doi:10.1158/1538-7445.AM2011-1407