Phosphatase PRL-3 Is a Direct Regulatory Target of TGFβ in Colon Cancer Metastasis

Metastasis causes most deaths from cancer yet mechanistic understanding and therapeutic options remain limited. Overexpression of the phosphatase PRL-3 is associated with metastasis of colon cancer. Here we show here that PRL-3 is a direct target of signaling by transforming growth factor β (TGFβ), which is broadly implicated in progression and metastasis. We found that suppression of PRL-3 expression by TGFβ was mediated by Smad-dependent inhibition of PRL-3 transcription at the level of promoter activity. PRL-3 activation stimulated PI3K/AKT signaling which caused resistance to stress-induced apoptosis. PRL-3 overexpression promoted metastatic colonization in an orthotopic mouse model of colon cancer, whereas PRK-3 knockdown reduced metastatic potential. Altered metastatic phenotypes were not derivative of primary tumor development or local invasion but could be attributed to PRL-3-mediated cell survival. Our findings suggest that inhibiting PRL-3 expression might be an important mechanism through which TGFβ suppresses metastasis in colon cancer. Additionally, our findings suggest that loss of TGFβ signaling, which occurs commonly during colon cancer progression, is sufficient to activate a PRL-3-mediated cell survival pathway that can selectively promote metastasis. Therefore, a major implication of our findings is that PRL-3 antagonists may offer significant value for anti-metastatic therapy in patients with colon cancer.