Haihe Wang, Samantha Yiling Quah, Jing Ming Dong, Edward Manser,
Jing Ping Tang, and Qi Zeng
PRL-3 is a metastasis-associated phosphatase. We and others have demonstrated that its overexpression increases cell motility and invasiveness. These phenotypic changes are reminiscent of the epithelial-mesenchymal transition (EMT) that occurs during embryonic development and oncogenesis. The EMT is a complex process that converts epithelia into migratory mesenchymal cells. We here attempt to unravel the underlying mechanistic basis of these phenomena. HeLa cells transiently expressing EGFP-PRL-3 (HeLa-PRL-3) exhibit reduced levels of paxillin. Similarly, CHO cells stably expressing myc-PRL-3 (CHO-PRL-3) also show marked reductions in paxillin, phospho-paxillin-Tyr31, and vinculin at focal adhesion complexes, and notable reductions in the levels of RhoA-GTP, Rac1-GTP, and F-actin filaments. DLD-1 human colorectal cancer cells engineered to express EGFP-PRL-3 (DLD-1-PRL-3) underwent changes consistent with EMT. In these cells, PRL-3 activates Akt and inactives GSK-3b as assessed by phospho-specific antibodies. PRL-3 upregulates mesenchymal markers: fibronectin, Snail and downregulates epithelial markers: E-cadherin, g-catenin (plakoglobin), and integrin-b3, which are major effectors in the EMT pathway. The changes in these EMT characteristics brought about by PRL-3 can be abrogated by the phosphoinositide 3 kinase (PI3K) inhibitor LY294002, implying that PRL-3 acts upstream of PI3K and could play an initiating role to trigger the EMT switch during cancer metastasis. In addition, PRL-3 can downregulate PTEN which is an important antagonist of PI3K, further reinforcing PI3K/Akt function in PRL-3 triggered EMT. Catalytically inactive PRL-3 (C104S) was impaired in the above PRL-3-mediated events, indicating that these properties require phosphatase activity. Targeting PRL-3 may thus be a useful strategy to impede cancer cell invasion and metastasis.
Published in Cancer Res 2007; 67: (7) pg.2922-6. April 1, 2007.
PRL-3 Down-regulates PTEN Expression and Signals through PI3K to Promote Epithelial-Mesenchymal Transition - Full Research Article(PDF) Click here to download.