Abstract 2384: Aberrant expression of PDZ binding kinase modulates human pancreatic cancer cell invasion

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths and projected to be the second leading cause of cancer deaths by 2030. Incidence to mortality ratio for PDAC is almost one suggesting its aggressive phenotype. The poor survival rate of PDAC patients is due to metastasis to distant organs, and therefore, recent focus has been aimed towards the identification of molecular targets that drives metastatic disease. We are investigating an under-studied kinase, PDZ-domain binding kinase (PBK) as a target for pancreatic cancer (PanCa) therapy. PBK is a dual-specificity serine/threonine kinase involved in mitosis and invasive behavior of cancer cells. It is expressed physiologically in testis, but aberrant expression results in an aggressive phenotype in a variety of cancers. Our results demonstrate that PBK expression varies across a panel of human PanCa cell lines, and directly correlates with their invasive ability. Similarly, a panel of patient-derived primary PanCa shows higher PBK levels associated with aggressive behavior and invasion. To assure specificity of PBK to this invasive phenotype, we measured the effect of PBK overexpression or knockdown on the PanCa lines’ invasive ability. Overexpression of PBK in low PBK expressing cells increased PanCa invasion ~10-fold, while PBK knockdown reduced invasive ability ~5-fold. Immunohistochemical analyses of resected human PanCa specimens revealed that PBK is present in the majority of human PanCa tissue samples tested but not in the adjacent normal pancreatic tissue. Interestingly, aberrant PBK localization was found in even early stages of PanCa development and was sustained throughout its progression. In search of molecular effectors of invasion regulated by the PBK, we examined various genes/proteins that are involved in cancer cell invasion and metastasis. RelB a well-known metastatic inducer in various cancers was found to be a major payer in PanCa and regulated by PBK. These data indicate a novel molecular pathway of PBK where its presence plays a role in invasion of human PanCa cells. Therefore, the role of PBK in promoting cancer cell invasion, combined with its general lack of expression in normal cells, nominates PBK as a potentially important therapeutic target for pancreatic cancer. Citation Format: Charles Hinzman, Jose Trevino, Partha P. Banerjee. Aberrant expression of PDZ binding kinase modulates human pancreatic cancer cell invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2384. doi:10.1158/1538-7445.AM2017-2384