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.
Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
Anders E
AE
Berglund
Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
Kristen E N
KE
Scott
Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
Weimin
W
Li
Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
Chunying
C
Yang
Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.|Department of Oncologic Sciences, University of South Florida, Tampa, Florida, USA.
Mario R
MR
Fernandez
Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
Franz X
FX
Schaub
Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.|Department of Oncologic Sciences, University of South Florida, Tampa, Florida, USA.
John L
JL
Cleveland
Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.|Department of Oncologic Sciences, University of South Florida, Tampa, Florida, USA.
Robert J
RJ
Rounbehler
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D007610:Kallikreins / Q000097:blood; D008297:Male; D008819:Mice, Nude; D060787:Neoplasm Grading; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013997:Time Factors; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D051816:Tristetraprolin; D025521:Tumor Suppressor Proteins; C497552:ZFP36 protein, human; D004317:Doxorubicin; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
TTP; metabolism; proliferation; prostate cancer; tristetraprolin