Abstract 5186: PPME1 is a potential novel molecular target in gastric and lung cancer.

Abstract

Abstract Protein phosphatase 2A (PP2A) is a human tumor suppressor, and it accounts for the majority of serine/threonine phosphatase activity which is tightly regulated via the methylation of carboxy-terminal of PP2A. Methylation at the carboxyterminal Leu 309 residue by S-adenosylmethionine-dependent leucine carboxyl methytransferase-1 (LCMT1) leads to the activation of PP2A, whilst demethylation of Leu 309 by specific protein phosphatase methylesterase-1 (PPME1) suppresses the PP2A activity. Recent evidence showed that PPME1 is up-regulated in glioblastoma patients and associated with a poor prognosis. In this study we profiled 131 Chinese gastric cancer (GC) samples and 124 Chinese non-small cell lung carcinoma (NSCLC) samples by Affy and aCGH to identify potential drug targets, and found PPME1 gene amplification in 3.8% of the GC samples and 3.1% of the NSCLC samples. The PPME1amplification correlated with its mRNA expression. In addition, we confirmed that PPME1 protein expressions were also elevated in the PPME1-amplified tumor samples indicated by immunohistochemistry as compared with corresponding adjacent non-tumor samples. To further investigate the role of PPME1 amplification in tumor growth, we utilized siRNA-mediated gene silencing approaches to specifically knock down PPME1 expression in the PPME1 amplified human cancer cell lines SNU668 (GC) and Oka-C1 (NSCLC). We found that suppression of the PPME1 expression resulted in significant inhibition of cell proliferation and induction of cell death in those cells. In contrast, little effects were observed on the cell growth and survival of non PPME1-amplified human cancer cells, MKN1 (GC) and HCC95 (NSCLC). Moreover, we showed that the PPME-1 knock-down also resulted in a decrease of PP2A demethylation at Leu309, which correlated with down-regulation of phosphorylation of MAPK and AKT in the cells. Taken together, our data indicate that PPME-1 could be an attractive therapeutic target for subsets of gastric and lung cancers. Citation Format: Jing Li, Sufang Han, Ziliang Qian, Xinying Su, Shuqiong Fan, Jiangang Fu, Charles Liu, Lucy Yin, Zeren Gao, Guanshan Zhu, Jingchuan Zhang, De-Hua Yu, Qunsheng Ji. PPME1 is a potential novel molecular target in gastric and lung 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 5186. doi:10.1158/1538-7445.AM2013-5186