Abstract 4935: PDZ–domain binding kinase promotes invasion in prostate cancer cells through up–regulation of matrix metalloproteinases–2 and –9.

Members of the protein kinase superfamily of enzymes modulate many of the facets of the tumor phenotype, such as survival, proliferation, invasion and metastasis. Genetic, epigenetic or regulatory alterations can result in aberrant kinase behavior; the targeted inhibition of which has been a growing focus in anti-cancer drug development. PDZ-domain binding kinase (PBK) is an under-studied, dual-specificity serine/threonine kinase that has been shown to play a key role in cell division and regulation of multiple signaling pathways. It is expressed physiologically in spermatogenic germ and proliferating neural precursor cells, as well as aberrantly in a variety of cancer types. However, the role of PBK in prostate cancer has not been clearly defined. We have found that PBK expression varies greatly across a panel of human prostate cancer cell lines. Interestingly, the level of expression of PBK in prostate cancer cells directly correlates with their invasive ability. Since matrix metalloproteinases (MMP) -2 and -9 are key invasive effectors in a variety of cancers, we investigated their protein levels in relation to that of PBK. Expression of exogenous PBK in low PBK-expressing prostate cancer cell lines (LNCaP and VCaP) significantly upregulated levels of both the propeptide and active forms of MMP-2 and MMP-9; conversely, knockdown of PBK expression in a high PBK-expressing prostate cancer cell line (PC3M) significantly down-regulated both forms of these two MMPs. To determine if a change in PBK levels produces a significant phenotypic effect, we measured the effect of PBK overexpression or knockdown on the prostate cancer cell lines’ invasive ability, as measured in a modified Boyden chamber invasion assay. Overexpression of PBK increased prostate cancer cell invasion approximately ten fold, while PBK knockdown reduced PC3M invasive ability more than three fold. Moreover, immunohistochemical analysis revealed that PBK is present in the majority of human prostate cancer samples tested but not at all in the benign or normal human prostate tissue. These data indicate a novel function of PBK where its presence plays a role in invasion of human prostate cancer cells through up-regulation of MMP-2 and MMP-9. Therefore, the role of PBK in promoting cell invasion, combined with its general lack of expression in normal cells, nominates PBK as a potentially important therapeutic target for prostate cancer. Citation Format: Joshua D. Brown-Clay, Deepika N. Shenoy, Partha P. Banerjee. PDZ–domain binding kinase promotes invasion in prostate cancer cells through up–regulation of matrix metalloproteinases–2 and –9. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4935. doi:10.1158/1538-7445.AM2013-4935