Role of gonadal adipose tissue from metabolic síndrome mice in prostate cáncer development

DE SIERVI, ADRIANA; BAS, DIANA; PORRETTI, JULIANA; DE SIERVI, ADRIANA; DE LUCA, PAOLA; BAS, DIANA; PASCUALI, NATALIA; PORRETTI, JULIANA; DALTON, GUILLERMO N.; DE LUCA, PAOLA; PASCUALI, NATALIA; DALTON, GUILLERMO N.; SACCA, PAULA; SCALISE, GEORGINA D.; MASSILLO, CINTIA; SACCA, PAULA; SCALISE, GEORGINA D.; MASSILLO, CINTIA

C.A.B.A

Congreso; Reunión Conjunta de Sociedades de Biociencias 2017; 2017

Sociedad Argentina de Investigación Clínica

Metabolic syndrome (MeS) increases prostate cancer (PCa) riskand aggressiveness. C-terminal binding protein 1 (CtBP1) is a transcriptionalco-repressor of tumor suppressor genes that is activatedby low NAD+/NADH ratio.Previously our group established a MeS and PCa mice model thatidentified to CtBP1 as a novel link associating both diseases. Moreover,we found that CtBP1 represses aromatase transcription, anenzyme that converts androgens to estrogens. Our hypothesis isthat gonadal adipose tissue (gWAT) from MeS mice is a biologicallyactive organ that contributes to PCa development by affecting the circulating levels of pro-inflammatory cytokines, estrogens andmiRNAs. To address this hypothesis, MeS was induced in C57BL/6male mice by chronically feeding with high fat diet (HFD). MeS increased30% mice body weight compared to CD fed animals. After15 weeks of diet, PCa TRAMP-C1 murine cells were injected s.c.on MeS and control mice. 12 weeks after cell inoculation mice weresacrificed and tumors, testes and gWAT were collected for RNA isolationand ex vivo co-cultures. Peripheral blood was obtained forbiochemical and hormone levels determinations. MeS significantlyincreased serum estradiol levels. Moreover estradiol (10 nM, 96 h)induced TRAMP-C1 proliferation in vitro. Given that the major sourcesof estradiol in mice are adipose tissue and testes, we analyzedthe expression of aromatase and other genes in these tissues byRT-qPCR. In gWAT we found that MeS dramatically decreasedCtBP1 and Cyclin D1 expression, without aromatase expression levelschanges. Notably, we found that MeS mice had twice as muchgWAT as control animals. Furthermore, we developed an ex vivoco-culture system using gWAT obtained from CD or HFD fed miceand TRAMP-C1 cells. gWAT from MeS mice induced the number oftumor cells compared to the co-culture from CD fed animals. Altogether,these results define a key role for gWAT in MeS mice thatimpact in PCa development