Cell Death & Disease最新文献

Mutant Ras oncoproteins, particularly KRAS, are among the most prevalent drivers of cancer. Small-molecule KRAS inhibitors have emerged as promising cancer therapeutics, yet resistance development remains a major hurdle. To overcome this challenge, we explored rational combination strategies aimed at enhancing therapeutic efficacy and durability. We show that the KRAS-G12C inhibitor Sotorasib synergizes with the CDK4/6 inhibitor Palbociclib to eliminate pancreatic ductal adenocarcinoma (PDAC) cells and organoids harboring KRAS-G12C mutations. This synergy was especially pronounced following drug washout, indicating a durable cellular response. Similar synergistic effects were observed in non-small-cell lung cancer (NSCLC) cells. Additionally, the KRAS-G12D inhibitor MRTX1133 cooperated with Palbociclib to suppress growth of KRAS-G12D-mutant PDAC cells. Mechanistically, the combinations induced sustained cell cycle arrest, marked by reduced RB phosphorylation, decreased E2F1 expression, and increased levels of CDKN1B/p27. Deletion of CDKN1B largely reversed the growth-inhibitory effect, highlighting its essential role in mediating the observed synergy. In an orthotopic, immunocompetent mouse model of PDAC, MRTX1133 significantly reduced tumor growth and extended survival; however, despite its ability to suppress RB phosphorylation, Palbociclib failed to enhance these effects. Single-cell RNA sequencing suggested that Palbociclib treatment induces tumor vascularization, perhaps contributing to the lack of drug synergy observed in vivo. In summary, our findings demonstrate the therapeutic potential of enhancing cell cycle restriction point activation in KRAS inhibitor-based therapies, while emphasizing the importance of placing combination therapies into a suitable context.

Iroquois Homeobox 3 (IRX3), a highly conserved member of the Iroquois homeobox gene family, has been implicated in obesity through its regulation of fat mass and obesity-associated (FTO) gene. Emerging evidence indicates that IRX3 plays critical roles in the development of some cancers, but the specific functions and molecular mechanisms of IRX3 in glioblastoma (GBM) remain unknown. Here, we demonstrate that IRX3 is highly expressed in GBM and significantly correlated with poor prognosis of patients. IRX3 promotes cell proliferation, colony formation, migration, and invasion in vitro and brain tumor growth in vivo. Mechanistically, IRX3 promotes the transcription of CDK14 (Cyclin Dependent Kinase 14) by binding to its promoter, which in turn stabilizes β-catenin expression through restraining its ubiquitination degradation, thereby activating the canonical Wnt/β-catenin pathway and promoting GBM growth. In addition, we identify LRP6 (LDL receptor-related protein 6) as a crucial regulatory factor in maintaining IRX3-mediated stabilization of β-catenin. Our results demonstrate that IRX3 serves as a promising biomarker for patients with GBM, and targeting the IRX3-CDK14-LRP6 axis may represent a viable treatment approach for GBM.

Gasdermins (GSDM) are pore-forming proteins that mediate pyroptosis, an inflammatory form of programmed cell death characterized by membrane permeabilization and the release of intracellular contents. Beyond their roles in host defense and immunity, recent studies have revealed critical contributions of GSDMs, particularly GSDMD and GSDME, to the pathogenesis of neurodegenerative disorders. Their functional scope has now expanded beyond executing cell death to roles in tissue regeneration and food tolerance. The recent discovery that intact, full-length GSDMs can form pores is prompting a reevaluation of long-standing models of gasdermin activation. How post-transcriptional modifications (PTMs) regulate this unconventional activity, and under what physiological or pathological contexts these alternative mechanisms are engaged, remains an open question. Moreover, the development of neutralizing biologics that specifically target GSDM pores opens new avenues for therapeutic intervention. In light of these emerging insights, this review will provide a comprehensive and up-to-date overview of recent breakthroughs in GSDM research. We highlight advances in the structural basis of GSDM activation and pore assembly. We also discuss how these mechanisms are involved in the pathogenesis of neurodegenerative diseases and therapeutic strategies based on the emerging small-molecule inhibitors and neutralizing biologics.

A major obstacle for the successful treatment of cancer is the presence or development of resistance mechanisms toward therapeutic intervention. In urothelial cancer, cisplatin-based regimens are still routinely employed, and multiple pathways contribute to chemoresistance. Since the identification of heat shock protein 90 (HSP90) as potential cancer target, various HSP90 inhibitors have been developed and evaluated in clinical trials. However, limited efficacy has been observed, mainly caused by dose-limiting toxicity and the concomitant induction of a cytoprotective heat shock response (HSR). To avoid this effect, inhibitors targeting the C-terminal domain (CTD) of HSP90 that do not elicit an HSR have been put forward. Additionally, the crosstalk between autophagy and HSP90 is currently being explored, since both processes work together in proteostasis, and the modulation of autophagy might be helpful in order to improve the efficacy of HSP90 inhibitors. We demonstrate that the second-generation small-molecule inhibitor VWK147 targeting HSP90 CTD dimerization induces cell death in both cisplatin-sensitive and cisplatin-resistant urothelial carcinoma cells. The treatment with VWK147 in these cells led to the destabilization of classical HSP90 client proteins without triggering an HSR. Additionally, we observe that VWK147 re-sensitizes resistant urothelial carcinoma cells to cisplatin and-in combination with mTOR inhibition-synergistically kills cisplatin-sensitive and -resistant cells, in contrast to what is observed upon treatment with the N-terminal domain-targeting HSP90 inhibitor 17-AAG. This synergy may be explained by VWK147-mediated inhibition of late autophagy events, and thus a blockade of autophagic flux. Finally, we also observed that VWK147 induces non-canonical LC3 lipidation, indicating that this compound exerts a broader effect on ion balance or pH of the endolysosomal system. VWK147 is a promising inhibitor that targets the C-terminal dimerization of HSP90 and simultaneously exhibits autophagy-modulating effects. This compound could potentially be an effective option for improving anti-cancer therapies and/or overcoming treatment resistance.

Mesenchymal stem cells (MSCs) are extensively utilised to treat inflammatory diseases because of their strong immunosuppressive functions. However, these functions are strongly affected by the inflammatory microenvironment in vivo, which limits the therapeutic effect of MSCs. The present study demonstrated that TNF-α impairs the immunosuppressive effect of MSCs on T-cell proliferation. Mechanistically, TNF-α treatment decreased the expression of the H3 deacetylase HDAC5 and then led to increased super-enhancer (SE) signals and increased expression of leukaemia inhibitory factor (LIF), which results in the dysfunction of MSCs' immunosuppressive effect. Intravenous infusion of MSCs overexpressing HDAC5 increased therapeutic efficacy in SKG mice with inflammatory arthritis. Notably, TNF-α downregulated HDAC5 by promoting WTAP-mediated m6A modification of HDAC5 mRNAs, which are subsequently regulated by YTHDF2 to reduce mRNA stability. Our results reveal a synergistic epigenetic regulatory mechanism between SEs and m6A modification of MSC immunosuppressive functions and provide a novel strategy to promote the clinical therapeutic potential of MSC infusion in inflammatory diseases.

The clearance of dead adipocytes in adipose tissue (AT) poses a major challenge due to their large size, which exceeds the phagocytic capacity of macrophages and prevents classical, anti-inflammatory efferocytosis. Instead, adipose tissue macrophages (ATMs) accumulate around dying adipocytes, forming crown-like structures (CLS), and engage in lysosomal exocytosis - the extracellular degradation of adipocytes. In this study, we used an ex vivo explant model of murine epididymal white AT, cultured over seven days to investigate pharmacological strategies that modulate lysosomal exocytosis. We observed a progressive increase in CLS formation, secretion of the lysosomal enzymes ß-Hexosaminidase A (HEXA) and lysosomal acid lipase (LAL), and surface abundance of LAMP1 and LAMP2, confirming ATMs as key mediators of this process. Notably, activation of lysosomal exocytosis with the mTOR inhibitor Rapamycin enhanced adipocyte clearance and significantly reduced inflammatory ATM abundance and TNF-α secretion. Bulk RNA sequencing of ATMs revealed a highly significant impact of Rapamyin on ATM proliferation. In contrast, inhibition of lysosomal exocytosis with PIKfyve inhibitor Apilimod or targeted inhibition of LAL using Lalistat-2 disrupted lysosomal function and promoted a pro-inflammatory ATM phenotype. Our findings highlight lysosomal exocytosis as a critical pathway for the resolution of dead adipocytes and the regulation of inflammation in adipose tissue. Pharmacological enhancement of this process may represent a promising therapeutic approach to attenuate inflammation in AT and its metabolic consequences, including insulin resistance and type 2 diabetes.

Bladder cancer is a common malignancy, and the insensitivity of advanced bladder cancer to cisplatin poses an imminent challenge to treatment. Our study aims to identify novel targets that mediate cisplatin responsiveness in bladder cancer. Accordingly, overexpression of the histone demethylase KDM4A in clinical cohorts was found in association with poor prognosis. Tissue culture and animal tests showed that KDM4A pis ro-proliferative in bladder cancer cells. Using co-immunoprecipitation and mass spectrometry methods, we identified that USP7 is an interacting partners in KDM4A protein complex, in which USP7 catalyzes KDM4A proteins deubiquitination that uncouples the proteasome-dependent degradation. In accordance, a positive correlation between USP7 and KDM4A protein expression was noted in bladder cancer clinical samples. Functional validation tests confirmed that USP7 and KDM4A act complementarily to drive bladder cancer cell proliferation. Importantly, cell and animal assays all evidenced that antagonizing the USP7-KDM4A axis would aggravate cisplatin-induced DNA damage and sensitize cisplatin responsiveness.