RESUMEN
The transcription factor STAT3 is a promising target for the treatment of non-small cell lung cancer (NSCLC). STAT3 activity is mainly dependent on phosphorylation at tyrosine 705 (pSTAT3-Y705), but the modulation on pSTAT3-Y705 is elusive. By screening a library of deubiquitinases (Dubs), we found that the Otub1 increases STAT3 transcriptional activity. As a Dub, Otub1 binds to pSTAT3-Y705 and specifically abolishes its K48-linked ubiquitination, therefore preventing its degradation and promoting NSCLC cell survival. The Otub1/pSTAT3-Y705 axis could be a potential target for the treatment of NSCLC. To explore this concept, we screen libraries of FDA-approved drugs and natural products based on STAT3-recognition element-driven luciferase assay, from which crizotinib is found to block pSTAT3-Y705 deubiquitination and promotes its degradation. Different from its known action to induce ALK positive NSCLC cell apoptosis, crizotinib suppresses ALK-intact NSCLC cell proliferation and colony formation but not apoptosis. Furthermore, crizotinib also suppresses NSCLC xenograft growth in mice. Taken together, these findings identify Otub1 as the first deubiquitinase of pSTAT3-Y705 and provide that the Otub1/pSTAT3-Y705 axis is a promising target for the treatment of NSCLC.
RESUMEN
Proteasomes are overexpressed in multiple myeloma (MM) and proteasomal inhibitors (PIs) have been widely used for the treatment of MM. PIs are reported to induce MM cell apoptosis but impair necroptosis. In the present study, we found that PIs MG132 and bortezomib induce MM cell pyroptosis, a novel type of cell death, in a GSDME-dependent manner. Lack of GSDME totally blocks PI-induced pyroptosis. Interestingly, we found that Caspase-3/6/7/9 are all involved in pyroptosis triggered by PIs because the specific inhibitor of each caspase ablates GSDME activation. PIs markedly reduce mitochondrial membrane potential. Moreover, PIs disrupt the interaction of Bcl-2 and BAX, induce cytochrome c release from mitochondria to cytosol and activate GSDME. Furthermore, we found that overexpression of an N-terminal portion of GSDME suffices to release cytochrome c from mitochondria and to activate Caspase-3/9, suggesting N-GSDME might penetrate the mitochondrial membrane. Consistent with Bcl-2 inhibition, BAX can induce MM cell pyroptosis in a GSDME-dependent manner. In accordance with these findings, inhibition of Bcl-2 synergizes with PIs to induce MM cell pyroptosis. Therefore, the present study indicates that PIs trigger MM cell pyroptosis via the mitochondrial BAX/GSDME pathway and provides a rationale for combined treatment of MM with Bcl-2 and proteasome inhibitors to increase therapeutic efficiency via induction of pyroptosis.
Asunto(s)
Mieloma Múltiple , Piroptosis , Humanos , Piroptosis/fisiología , Inhibidores de Proteasoma/farmacología , Proteína X Asociada a bcl-2/metabolismo , Caspasa 3/metabolismo , Mieloma Múltiple/tratamiento farmacológico , Citocromos c/metabolismoRESUMEN
The PTEN/AKT/mTOR signaling pathway is frequently dysregulated in non-small cell lung cancer (NSCLC), but the mechanisms are not well-understood. The present study found that the ubiquitin ligase TRIM25 is highly expressed in NSCLC tissues and promotes NSCLC cell survival and tumor growth. Mechanistic studies revealed that TRIM25 binds to PTEN and mediates its K63-linked ubiquitination at K266. This modification prevents the plasma membrane translocation of PTEN and reduces its phosphatase activity therefore accumulating PI(3,4,5)P3. TRIM25 thus activates the AKT/mTOR signaling. Moreover, we found that the antibacterial nitroxoline can activate PTEN by reducing its K63-linked polyubiquitination and sensitizes NSCLC to cisplatin-induced apoptosis. This study thus identified a novel modulation on the PTEN signaling pathway by TRIM25 and provides a potential target for NSCLC treatment.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/patología , Proteínas de Unión al ADN/metabolismo , Neoplasias Pulmonares/patología , Fosfohidrolasa PTEN/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Cisplatino/farmacología , Humanos , Nitroquinolinas/farmacología , Monoéster Fosfórico Hidrolasas/fisiología , ARN Interferente Pequeño/metabolismo , Ubiquitinación/fisiologíaAsunto(s)
Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugía , Neoplasias de la Vulva/patología , Neoplasias de la Vulva/cirugía , Adulto , Biopsia con Aguja , Procedimientos Quirúrgicos Dermatologicos/métodos , Femenino , Humanos , Inmunohistoquímica , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Pronóstico , Enfermedades Raras , Resultado del TratamientoRESUMEN
OBJECTIVE: To explore treatment strategy for complex Schatzker â £ tibial plateau fracture. METHODS: Forty-one patients with complex Schatzker type â £ tibial plateau fractures were treated from January 2016 to January 2021, including 28 males and 13 females, aged from 19 to 65 years old with an average of (35.3±19.8) years old. Individualized treatment plan was developed according to preoperative imaging characteristics, medial surgical approach was mainly combined with other auxiliary incisions. Posteromedial inverted L approach was used in 18 patients, posteromedial approach and anterolateral extended approach in 19 patients, and posteromedial approach with anterolateral and lateral condylar osteotomy in 4 patients. Articular surface and facture healing were observed, range of knee joint motion was measured at 12 months after opertaion, and function of knee joint was evaluated by Lysholm scoring system. RESULTS: Forty-one patients were followed up for 12 to 26 months with an average of (13.3±6.8) months. Twenty-nine patients and 10 patients were obtained complete fracture healing at 6 and 12 months after operation respectively, and fracture healing time was 4 to 13 months with an average of (5.0±3.7) months. Two patients occurred posterior medial internal fixation failure and varus deformity of knee joint, and the fracture healed and varus deformity was corrected after the second operation. Range of knee joint motion was (118±29) °, and Lysholm score was(83.0±16.0) points. CONCLUSION: Individualized treatment should be reasonably selected for complex Schatzker â £ tibial plateau fractures, the characteristics of lateral plateau fractures are an important reference for selecting surgical approaches, the effective fixation of posteromedial bone blocks should be pay full attention, and the overall treatment results are satisfied.
Asunto(s)
Fracturas de la Tibia , Fracturas de la Meseta Tibial , Masculino , Femenino , Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Adolescente , Placas Óseas , Fracturas de la Tibia/cirugía , Resultado del Tratamiento , Articulación de la Rodilla/cirugía , Fijación Interna de Fracturas/métodos , Estudios RetrospectivosRESUMEN
Human oncogenic papillomaviruses (HPV) have an increasingly prominent role in the genesis of many cancers. The oncogenic mechanisms associated with HPV are now better known and make it possible to explain the etiopathogenesis of the association. HPV status is now sought for certain cancers and conditions both prognosis and management of patients. Preventive antiviral vaccination has become a real public health issue and aims to effectively reduce the prevalence of cervical, anal and oropharynx cancer, HPV-associated. However, vaccination against HPV still lags behind. The purpose of this review is to redefine the involvement of HPV in several cancers as well as current therapeutic challenges of HPV-related cancers, notably in term of prevention.