Prostate tumor growth is impaired by CtBP1 depletion in high-fat diet-fed mice.
OBJECTIVE
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.


METHODS
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.
Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, IBYME-CONICET; Laboratorio de Inflamación y Cáncer, Departamento de Química Biologica, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), IQUIBICEN - CONICET;
Cristian P
CP
Moiola
Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, IBYME-CONICET; Laboratorio de Inflamación y Cáncer, Departamento de Química Biologica, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), IQUIBICEN - CONICET;
Paola
P
De Luca
Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, IBYME-CONICET; Laboratorio de Inflamación y Cáncer, Departamento de Química Biologica, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), IQUIBICEN - CONICET;
Florencia
F
Zalazar
Laboratorio de Inflamación y Cáncer, Departamento de Química Biologica, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), IQUIBICEN - CONICET;
Javier
J
Cotignola
Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), and Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET;
Santiago A
SA
Rodríguez-Seguí
Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Kevin
K
Gardner
Departamento de Patología, Instituto de Estudios Oncológicos, Academia Nacional de Medicina;
Roberto
R
Meiss
Departamento de Patología, Instituto de Estudios Oncológicos, Academia Nacional de Medicina;
Pablo
P
Vallecorsa
Laboratorio de Endocrinología Molecular y Transducción de Señales, IBYME-CONICET, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), IQUIBICEN - CONICET;
Omar
O
Pignataro
Hospital de Clínicas "José de San Martín", Buenos Aires, Argentina; and.
Osvaldo
O
Mazza
Laboratorio de Inflamación y Cáncer, Departamento de Química Biologica, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), IQUIBICEN - CONICET;
Elba S
ES
Vazquez
Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, IBYME-CONICET; Laboratorio de Inflamación y Cáncer, Departamento de Química Biologica, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), IQUIBICEN - CONICET; adesiervi@qb.fcen.uba.ar.
Adriana
A
De Siervi
D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002448:Cell Adhesion; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D020869:Gene Expression Profiling; D012739:Gonadal Steroid Hormones / Q000494:pharmacology; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008819:Mice, Nude; D009765:Obesity / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D012739:Gonadal Steroid Hormones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein