Abstract 1976: Targeting the PP2A tumor suppressor for the treatment of human pancreatic cancer.

Abstract

Abstract Pancreatic cancer is a disease with a high rate of mortality, as it is generally diagnosed in the advanced stages when few effective treatments are available. Given the clinical aggressivity of this disease and the lack of good treatment options, the development of new therapeutic agents for the treatment of pancreatic cancer is of the upmost importance. Recent reports have suggested that disruption of several key signal transduction pathways is important for the development of pancreatic cancer. Many of these pathways are negatively regulated by PP2A, a phosphatase that plays a role in many cellular processes, and whose inhibition is essential for cell transformation. PP2A inhibition can occur through inactivation by viral oncogenes, mutation of specific subunits, or by overexpression of endogenous inhibitors, including SET (also known as I2PP2A) and Cellular Inhibitor of PP2A (CIP2A). Here, we show that SET and CIP2A are frequently overexpressed in human pancreatic cancer cells and primary patient samples. This overexpression results in decreased PP2A activity, and overexpression and stabilization of a key PP2A target, c-Myc. Knockdown of SET or CIP2A increases PP2A activity and reduces tumorigenic potential. Furthermore, inhibition of SET using a peptide mimetic (OP449) in pancreatic cancer cell lines increases PP2A activity, reduces migration and invasion, and decreases tumorigenic potential. Thus, antagonizing SET and CIP2A could be an innovative approach for the treatment of human pancreatic cancer. Citation Format: Amy Farrell, Colin Daniel, Zhiping Wang, Brittany Allen-Petersen, Dale Christensen, Brett Sheppard, Charles D. Lopez, Rosalie Sears. Targeting the PP2A tumor suppressor for the treatment of human pancreatic cancer. [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 1976. doi:10.1158/1538-7445.AM2013-1976