Tristetraprolin disables prostate cancer maintenance by impairing proliferation and metabolic function

Tristetraprolin (TTP) is an RNA-binding protein that post-transcriptionally suppresses gene expression by delivering mRNA cargo to processing bodies (P-bodies) where the mRNA is degraded. TTP functions as a tumor suppressor in a mouse model of B cell lymphoma, and in some human malignancies low TTP expression correlates with reduced survival. Here we report important prognostic and functional roles for TTP in human prostate cancer. First, gene expression analysis of prostate tumors revealed low TTP expression correlates with patients having high-risk Gleason scores and increased biochemical recurrence. Second, in prostate cancer cells with low levels of endogenous TTP, inducible TTP expression inhibits their growth and proliferation, as well as their clonogenic growth. Third, TTP functions as a tumor suppressor in prostate cancer, as forced TTP expression markedly impairs the tumorigenic potential of prostate cancer cells in a mouse xenograft model. Finally, pathway analysis of gene expression data suggested metabolism is altered by TTP expression in prostate tumor cells, and metabolic analyses revealed that such processes are impaired by TTP, including mitochondrial respiration. Collectively, these findings suggest that TTP is an important prognostic indicator for prostate cancer, and augmenting TTP function would effectively disable the metabolism and proliferation of aggressive prostate tumors. Overall design: PC-3 cells were infected with a pRetroX-Tet-On-Advanced retrovirus and selected for by G418 resistance. Then the G418-resistant cells were secondarily infected with either a pRetroX-Tight-pPGK-tdTomato or a pRetroX-Tight-TTP-pPGK-tdTomato retrovirus and selected for by the expression of tdTomato. G418-resistant, tdTomato-positive cells were used for experiments, in triplicate for each cell type. Cells were treated with 300 ng/ml doxycycline (Dox) for 4h prior to collection. Cells infected with pRetroX-Tight-pPGK-tdTomato were used as controls.

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Berglund AE, Scott KE, Li W, Yang C, Fernandez MR, Schaub FX, Cleveland JL, Rounbehler RJ