It is critical to understand the molecular mechanisms underlying the migration and invasiveness of prostate cancer (PC) for improving the outcome of therapy. A relationship of pituitary tumor-transforming gene 1 (Pttg1) and matrix metalloproteinase 13 (MMP13) in PC as well as their roles in the metastases of PC has not been studied. Here, we reported significantly higher levels of Pttg1 and MMP13 in the resected PC specimens, compared to the adjacent normal prostate tissue from the same patient. Interestingly, Pttg1 and MMP13 levels strongly correlated with each other. In vitro, Pttg1 activated MMP13, which determined PC cell invasiveness. However, Pttg1 levels were not significantly affected by MMP13. Furthermore, the Pttg1-activated MMP13 in PC cells was significantly suppressed by inhibition of PI3k/Akt, but not ERK/MAPK or JNK pathways. Together, our data suggest that Pttg1 may increase PC cell metastasis by MMP13, and highlight Pttg1/MMP13 axis as a promising therapeutic target for PC treatment.