RESUMEN
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.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Transportadores de Ácidos Dicarboxílicos/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Poliaminas/metabolismo , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Anciano , Anciano de 80 o más Años , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Transportadores de Ácidos Dicarboxílicos/genética , Estudios de Seguimiento , Humanos , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Mitocondrias/metabolismo , Mitocondrias/patología , Proteínas de Transporte de Membrana Mitocondrial/genética , Metástasis de la Neoplasia , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Pronóstico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Transducción de Señal , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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.
Asunto(s)
Susceptibilidad a Enfermedades , Factor I del Crecimiento Similar a la Insulina/metabolismo , Neoplasias/etiología , Neoplasias/metabolismo , Ubiquitinas/metabolismo , Adhesión Celular , Proteínas de Ciclo Celular/metabolismo , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Vía de Señalización Hippo , Humanos , Mecanotransducción Celular , Modelos Biológicos , Neoplasias/mortalidad , Neoplasias/patología , Pronóstico , Unión Proteica , Procesamiento Proteico-Postraduccional , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Factores de Transcripción/metabolismo , beta Catenina/metabolismo , Proteínas con Repetición de beta-Transducina/metabolismo , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
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.