PRL-3 dephosphorylates p38 MAPK to promote cell survival under stress.

Hypoxia within the tumor microenvironment, which leads to excessive ROS and genomic instability, is one of the hallmarks of cancer, contributing to self-renewal capability, metastasis, and radio-chemotherapy resistance. PRL-3 is an oncoprotein involved in various pro-survival signaling pathways, such as Ras/Erk, PI3K/Akt, Src/STAT, mTORC1 and JAK/STAT. However, there is little evidence connecting PRL-3-mediated apoptosis resistance to tumor microenvironmental stress. In this study, by profiling the PRL-3 expression of multiple tumor types retrieved from public databases (TCGA and NCBI GEO), we confirmed the oncogenic function of PRL-3 and found an intriguing connection between PRL-3 expression and tumor hypoxia signature genes. Moreover, by using CoCl 2 , a hypoxia mimetic and ROS inducer, we discovered that cells stably expressing PRL-3, but not catalytically-inactive mutant PRL-3 C104S, showed significant resistance to CoCl 2 -induced apoptosis. This resistance to apoptosis was found to depend on p38 MAPK signaling and was further confirmed in other conditions of microenvironmental stress, including UV, H 2 O 2 and hypoxia. Mechanistically, we proved that PRL-3 is a direct phosphatase of p38 MAPK under stressed conditions. Additionally, in mouse models of tumor metastasis, higher lung metastatic burden and lower p38 MAPK phosphorylation were found in mice seeded with GFP-PRL-3 expressing cells compared with those seeded with GFP-Ctrl cells. Taken together, our study identified a critical role of RPL-3 in tumorigenesis by negatively regulating p38 MAPK activity in order to facilitate tumor cell adaptation to a hypoxic stressed tumor microenvironment and suggests that PRL-3 could serve as a promising novel therapeutic target for cancer patients. [Display omitted] • PRL-3 is upregulated and plays an oncogenic role in different types of cancer. • PRL-3 is positively correlated with hypoxia signature genes in pan-cancer database. • PRL-3 overexpression leads to resistance to hypoxia-induced apoptosis via p38 MAPK. • PRL-3 is the direct phosphatase of p38 MAPK under stress conditions. • PRL-3 suppresses p38 phosphorylation and promotes tumor metastasis in mouse model. [ABSTRACT FROM AUTHOR]