1. Prostate tumor growth is impaired by CtBP1 depletion in high-fat diet-fed mice.
- Author
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Moiola CP, De Luca P, Zalazar F, Cotignola J, Rodríguez-Seguí SA, Gardner K, Meiss R, Vallecorsa P, Pignataro O, Mazza O, Vazquez ES, and De Siervi A
- Subjects
- Alcohol Oxidoreductases genetics, Alcohol Oxidoreductases metabolism, Animals, Apoptosis, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Blotting, Western, Cell Adhesion, Cell Proliferation, Cell Transformation, Neoplastic drug effects, Cell Transformation, Neoplastic pathology, Chromatin Immunoprecipitation, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Gene Expression Profiling, Gonadal Steroid Hormones pharmacology, Humans, Immunoenzyme Techniques, Male, Metabolic Syndrome etiology, Metabolic Syndrome pathology, Mice, Mice, Nude, Obesity etiology, Obesity pathology, Oligonucleotide Array Sequence Analysis, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, RNA, Messenger genetics, RNA, Small Interfering genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Alcohol Oxidoreductases antagonists & inhibitors, DNA-Binding Proteins antagonists & inhibitors, Diet, High-Fat adverse effects, Metabolic Syndrome prevention & control, Obesity prevention & control, Prostatic Neoplasms prevention & control
- Abstract
Purpose: Clinical and epidemiologic data suggest that obesity is associated with more aggressive forms of prostate cancer, poor prognosis, and increased mortality. C-terminal-binding protein 1 (CtBP1) is a transcription repressor of tumor suppressor genes and is activated by NADH binding. High calorie intake decreases intracellular NAD(+)/NADH ratio. The aim of this work was to assess the effect of high-fat diet (HFD) and CtBP1 expression modulation over prostate xenograft growth., Experimental Design: We developed a metabolic syndrome-like disease in vivo model by feeding male nude mice with HFD during 16 weeks. Control diet (CD)-fed animals were maintained at the same conditions. Mice were inoculated with PC3 cells stable transfected with shCtBP1 or control plasmids. Genome-wide expression profiles and Gene Set Enrichment Analysis (GSEA) were performed from PC3.shCtBP1 versus PC3.pGIPZ HFD-fed mice tumors., Results: No significant differences were observed in tumor growth on CD-fed mice; however, we found that only 60% of HFD-fed mice inoculated with CtBP1-depleted cells developed a tumor. Moreover these tumors were significantly smaller than those generated by PC3.pGIPZ control xenografts. We found 823 genes differentially expressed in shCtBP1 tumors from HFD-fed mice. GSEA from expression dataset showed that most of these genes correspond to cell adhesion, metabolic process, and cell cycle., Conclusions: Metabolic syndrome-like diseases and CtBP1 expression cooperate to induce prostate tumor growth. Hence, targeting of CtBP1 expression might be considered for prostate cancer management and therapy in the subset of patients with metabolic syndromes., (©2014 American Association for Cancer Research.)
- Published
- 2014
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