Tpl2 induces castration resistant prostate cancer progression and metastasis

Progression to metastatic castration resistant prostate cancer (CRPC) is the major lethal pathway of prostate cancer (PC). Herein, we demonstrated that tumor progression locus 2 (Tpl2) kinase is the fundamental molecule provoking progression and metastasis of CRPC. Tpl2 upregulates CXCR4 and focal adhesion kinase (FAK) to activate CXCL12/CXCR4 and FAK/Akt signalling pathway. Consequently, epithelial-mesenchymal transition (EMT) and stemness of androgen depletion independent (ADI) PC cells are induced, which is dependent on the kinase activity of Tpl2. In vitro, proliferation, clonogenicity, migration, invasion and chemoresistance of ADI PC cells were enhanced by Tpl2. In vivo, Tpl2 overexpression and downregulation showed significant stimulatory and inhibitory effects on tumorigenic and metastatic potential of ADI PC cells, respectively. Moreover, the prognostic effects of Tpl2 and expressional correlation between Tpl2 and EMT-related molecules/CXCR4 were validated in clinical PC databases. Since Tpl2 exerts metastatic progression promoting activities in CRPC, Tpl2 could serve as a novel therapeutic target for metastatic CRPC. What's New? Prostate cancer turns deadly when it metastasizes and the removal of available androgens - castration -- can no longer hinder it. In this paper, the authors report that the kinase Tpl2 spurs this transition to metastasis. Not only did they find more Tpl2 mRNA in metastatic cells than in non-metastatic, they also showed that Tpl2 upregulates two signaling pathways integral to metastasis. The kinase activity of Tpl2 also support the development of stem cell capabilities in the cancer cells. These results suggest that targeting Tpl2 could impede the spread of prostate cancer.