CtBP1 is implicated in prostate tumor development in a metabolic syndrome-like disease in vivo model

MOIOLA C; DE LUCA P; ZALAZAR F; RODRIGUEZ SEGUI S; COTIGNOLA J; MEISS R; VAZQUEZ E; DALTON, N; LABANCA E; GARDNER K; DE SIERVI A

Congreso; AACR Annual Meeting 2014; 2014

Clinical and epidemiological data suggest that obesity is associated with more aggressive forms of prostate cancer (PCa), poor prognosis and increased mortality. In addition, high calorie intake decreases intracellular NAD+/NADH ratio. C-terminal Binding Protein 1 (CtBP1) is a transcription repressor of several important tumor suppressor genes and is activated by NADH binding. The aim of this work was to assess the effect of a high fat diet (HFD) and CtBP1 expression modulation over PCa tumor development in a murine xenograft model. We developed a metabolic syndrome-like disease in vivo model. Male nude mice fed with HFD or control diet (CD) for 16 weeks showed hypercholesterolemia, low testosterone serum levels, liver steatosis and glomeruli enlargement with edema at the kidney ephitelium collecting duct. In addition, at week 12 of diet, prostate tumor PC3 cells stable transfected with shCtBP1 or control (pGIPZ) plasmids were s.c. inoculated into randomly divided mice groups. 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; even more these tumors were significantly smaller than those generated by PC3.pGIPZ control xenografts. Furthermore, CtBP1 depletion in xenograft tumors was validated by IHQ and RTqPCR. Genome-wide expression profiles (HUGENE ST1.0 Affymetrix) from PC3.shCtBP1 versus PC3.pGIPZ HFD fed mice tumors showed 823 genes differentially expressed (1.5 fold change and p < 0.05). By biological process GO classification, we found that most of these genes correspond to cell adhesion, metabolic process, apoptosis and cell cycle among others GO terms. In addition, we performed Gene Set Enrichment Analyses (GSEA) from our expression datasets and contrasted our results using MSigDB (C2 and C5 gene sets collection). We identified gene sets associated with metabolic and cellular processes. Interestingly, E-cadherin (CDH1) and aromatase (CYP19A1) expression were up-regulated in CtBP1 depleted tumors, and we validated this evidence by RT-qPCR. Our results suggested that metabolic syndrome-like diseases and CtBP1 expression might cooperate to PCa tumor development. Hence, CtBP1 expression might be considered for PCa management and therapy in the subset of patient with metabolic syndromes.