Abstract 136: PTEN phosphatase inhibits metastasis through negatively affecting Entpd5/IGF1R pathway

Abstract

Abstract Migration of cancer cell is the key event in metastasis. Recent data suggest that PTEN phosphatase activity may be required for inhibiting cell migration; however, little in vivo experimental evidence exists directly demonstrating the efficacy of PTEN phosphatase in tumor metastasis. We showed here that PTEN loss was correlated with progression to metastatic state using tissue array analysis and UV-irradiated HGF/SF transgenic-PTEN deficient mouse melanoma model. Analysis of various human melanoma cell lines demonstrated that PTEN expression was related to metastatic behavior. To further dissect the role of PTEN activity in metastasis, we have established a model system containing mutant PTEN with various phosphatase activities. We found that wild type PTEN could inhibit cell motility and invasiveness. Moreover, wild type PTEN was able to reduce metastatic potential of melanoma cells in a dose-dependent manner; in contrast, PTEN phosphatase dead mutant promoted metastatic behavior of melanoma cell. To gain more insight into the regulation of tumor cell migration, invasion and metastasis by PTEN, we performed a microarray analysis of cells with various PTEN phosphatase mutants. We found that a protein N-glycosylation and folding promoter, Entpd5 was negatively regulated by PTEN phosphatase. Down regulation of Entpd5 by shRNA in cells with PTEN phosphatase dead mutant blocked PTEN phosphatase dead mutant mediated tumor metastasis in vivo, promoted cell ER stress and growth inhibition as well as reduction of IGF1R. In contrast, overexpression of Entpd5 in cell with PTEN wild-type form enhanced PTEN wild-type-inhibited tumor metastasis in vivo, inhibited cell ER stress, promoted cell growth and abundance of IGF1R. We provide mechanistic insight toward regulation of metastasis by PTEN phosphatase and demonstrate a link between PTEN and Entpd5/IGF1R activation in metastatic process. Citation Format: Yanlin Yu. PTEN phosphatase inhibits metastasis through negatively affecting Entpd5/IGF1R pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 136. doi:10.1158/1538-7445.AM2014-136