RESUMO
Although tumorigenesis is dependent on the reprogramming of cellular metabolism, the metabolic pathways engaged in the formation of metastases remain largely unknown. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) plays a pleiotropic role in the control of cancer cell metabolism and has been associated with a good prognosis in prostate cancer. Here, we show that PGC1α represses the metastatic properties of prostate cancer cells via modulation of the polyamine biosynthesis pathway. Mechanistically, PGC1α inhibits the expression of c-MYC and ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme for polyamine synthesis. Analysis of in vivo metastases and clinical data from patients with prostate cancer support the proposition that the PGC1α/c-MYC/ODC1 axis regulates polyamine biosynthesis and prostate cancer aggressiveness. In conclusion, downregulation of PGC1α renders prostate cancer cells dependent on polyamine to promote metastasis. SIGNIFICANCE: These findings show that a major regulator of mitochondrial metabolism controls polyamine synthesis and prostate cancer aggressiveness, with potential applications in therapy and identification of new biomarkers.
Assuntos
Biomarcadores Tumorais/metabolismo , Transportadores de Ácidos Dicarboxílicos/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Poliaminas/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Transportadores de Ácidos Dicarboxílicos/genética , Seguimentos , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas de Transporte da Membrana Mitocondrial/genética , Metástase Neoplásica , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Prognóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Transdução de Sinais , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Ubiquitin domain-containing protein 1 (UBTD1) is highly evolutionary conserved and has been described to interact with E2 enzymes of the ubiquitin-proteasome system. However, its biological role and the functional significance of this interaction remain largely unknown. Here, we demonstrate that depletion of UBTD1 drastically affects the mechanical properties of epithelial cancer cells via RhoA activation and strongly promotes their aggressiveness. On a stiff matrix, UBTD1 expression is regulated by cell-cell contacts, and the protein is associated with ß-catenin at cell junctions. Yes-associated protein (YAP) is a major cell mechano-transducer, and we show that UBTD1 is associated with components of the YAP degradation complex. Interestingly, UBTD1 promotes the interaction of YAP with its E3 ubiquitin ligase ß-TrCP Consequently, in cancer cells, UBTD1 depletion decreases YAP ubiquitylation and triggers robust ROCK2-dependent YAP activation and downstream signaling. Data from lung and prostate cancer patients further corroborate the in cellulo results, confirming that low levels of UBTD1 are associated with poor patient survival, suggesting that biological functions of UBTD1 could be beneficial in limiting cancer progression.
Assuntos
Suscetibilidade a Doenças , Fator de Crescimento Insulin-Like I/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Ubiquitinas/metabolismo , Adesão Celular , Proteínas de Ciclo Celular/metabolismo , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Via de Sinalização Hippo , Humanos , Mecanotransdução Celular , Modelos Biológicos , Neoplasias/mortalidade , Neoplasias/patologia , Prognóstico , Ligação Proteica , Processamento de Proteína Pós-Traducional , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , beta Catenina/metabolismo , Proteínas Contendo Repetições de beta-Transducina/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
Angioplasty with or without stenting has become a well-established procedure to treat transplant renal artery stenosis (TRAS). We evaluated our experience on postoperative outcomes following the intervention and identified potential predictive factors of TRAS recurrence. Consecutive patients who underwent endovascular treatment of TRAS were retrospectively reviewed. The study end points were the technical success, 30-day postoperative complications, and the estimated glomerular filtration rate (eGFR). Thirty-two patients underwent endovascular treatment for TRAS. The technical success rate was 96.6%. Complications were observed for 7 (21.9%) patients: 4 had a dissection, 2 a pseudoaneurysm, and 1 (3.1%) patient developed an acute pulmonary edema. The mean eGFR significantly increased at 7 days, 3 months, and 6 months postintervention (43.1, 44.9, and 44.3 vs 33.9 mL/min/1.73 m2 preoperatively, P < .05). The TRAS recurrence was observed in 7 (21.9%) patients. These patients had significantly higher preoperative peak systolic velocity and systolic rise time (5 vs 4 m/s, P = .0383 and 103 vs 80 milliseconds, P = .0148, respectively). Endovascular treatment of TRAS is associated with high technical success and significant improvement in renal function. Further studies are required to confirm predictive factors of TRAS recurrence following endovascular treatment.
