Proteasomal inhibitors induce myeloma cell pyroptosis via the BAX/GSDME pathway.

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.

TRIM25 activates AKT/mTOR by inhibiting PTEN via K63-linked polyubiquitination in non-small cell lung cancer.

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.

[Treatment analysis of complex Schatzker type â £ tibial plateau fractures].

OBJECTIVE: To explore treatment strategy for complex Schatzker Ⅳ tibial plateau fracture. METHODS: Forty-one patients with complex Schatzker type Ⅳ 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 Ⅳ 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.

[HPV: Carcinogenic implications and preventive measures]. / Le papillomavirus : implications carcinologiques et mesures préventives.

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.