Tristetraprolin disables prostate cancer maintenance by impairing proliferation and metabolic function

Abstract

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.

The Tristetraprolin Family of RNA-Binding Proteins in Cancer: Progress and Future Prospects

“…TTP has also been suggested as a promising biomarker for prostate cancer risk assessment. TTP expression was markedly reduced in metastatic prostate cancer compared to primary tumors [64]. Men with low TTP-expressing primary prostate cancer had significantly increased chances of biochemical reoccurrence in this study.…”

“…Low-TTP in prostate cancer correlated with increased recurrence. Induced TTP expression reduced cell proliferation, clonogenic growth, and tumorigenic potential of prostate cancer cells [64].…”

The ARE-binding protein Tristetraprolin (TTP) is a novel target and mediator of calcineurin tumor suppressing function in the skin

“…Next, we sought to further understand the mechanism of the tumor-suppressing function of TTP in the skin since increased inflammation was observed in grafts with knockdown of TTP in keratinocytes. We analyzed changes of cytokine expression and of metabolic genes, which have been reported to play crucial roles in TTP tumor-suppression function[ 18 , 23 ], in SCC13 skin tumor cells with modulations of TTP expression levels. We found that the knockdown of TTP in SCC13 cells induced the expression of the cytokines IL-8, TNFα, VEGF and COX2 ( S9A Fig ) as well as genes involved in metabolic pathways including the pyruvate dehydrogenase complex (PDK1), the citric acid cycle (IDH3A), the electron transport chain (GPD2), branched-chain amino acid metabolism (BCKDHB), purine biosynthesis (ADSS) and the pyrimidine salvage pathway (CMPK1) ( S9B Fig ).…”

“…The aberrant over-expression of ARE-containing genes plays a crucial role in the initiation and progression of tumorigenesis [ 22 , 34 , 35 ]. A loss or decreased expression of TTP was observed in various epithelial tumors including breast, cervix, colon, liver, prostate and other cancers [ 18 , 22 , 23 , 35 , 36 ]. More and more evidence shows that the loss of TTP promotes tumorigenesis through multiple cancer-associated progressions including enhancing cancer cell proliferation by regulating IL-8, VEGF and COX2 production, and accelerating the cell cycle [ 18 ].…”

“…TTP is believed to promote the ARE-mediated decay of cytokine mRNA [ 16 , 20 ]. Recent studies have suggested that TTP plays a tumor suppressing function in cancer development [ 18 , 21 – 23 ]. The deregulation of TTP has been found to play an important role in the progression of various cancers, including inflammation-related cancers, as well as in processes of proliferation, apoptosis, angiogenesis, metastasis, invasion and chemotherapy resistance [ 18 , 22 ].…”