Cell Death & Disease最新文献

Gastric cancer (GC) is one of the most lethal malignancies worldwide. Despite extensive efforts to develop novel therapeutic targets, effective drugs for GC remain limited. Recent studies have indicated that Lipocalin (LCN)2 abnormalities significantly impact GC progression; however, its regulatory network remains unclear. Our study investigates the functional role and regulatory mechanism of action of LCN2 in GC progression. We observed a positive correlation between LCN2 expression, lower GC grade, and better prognosis in patients with GC. LCN2 overexpression suppressed GC proliferation and metastasis both in vitro and in vivo. Transcriptome sequencing identified secreted protein acidic and rich in cysteine (SPARC) as a pivotal downstream target of LCN2. Mechanistically, c-Jun acted as a transcription factor inducing SPARC expression, and LCN2 downregulated SPARC by inhibiting the JNK/c-Jun pathway. Moreover, LCN2 bound to its receptor, 24p3R, via autocrine signaling, which directly inhibited JNK phosphorylation and then inhibited the JNK/c-Jun pathway. Finally, analysis of clinical data demonstrated that SPARC expression correlated negatively with lower GC grade and better prognosis, and that LCN2 expression correlated negatively with p-JNK, c-Jun, and SPARC expression in GC. These findings suggest that the LCN2/24p3R/JNK/c-Jun/SPARC axis is crucial in the malignant progression of GC, offering novel prognostic markers and therapeutic targets.

Ninjurin-1 (NINJ1), initially identified as a stress-induced protein in neurons, recently emerged as a key mediator of plasma membrane rupture (PMR) during apoptosis, necrosis, and pyroptosis. However, its involvement in ferroptosis is less well elucidated. Here, we demonstrate that NINJ1 also plays a crucial role in ferroptosis, but through a distinct mechanism. NINJ1 knockdown significantly protected cancer cells against ferroptosis induced only by xCT inhibitors but no other classes of ferroptosis-inducing compounds (FINs). Glycine, known to inhibit canonical NINJ1-mediated membrane rupture in other cell deaths, had no impact on ferroptosis. A compound screen revealed that the ferroptosis protective effect caused by NINJ1 knockdown can be abolished by pantothenate kinase inhibitor (PANKi), buthionine sulfoximine (BSO), and diethylmaleate (DEM). These results suggest that this ferroptosis protection is mediated via Coenzyme A (CoA) and glutathione (GSH), both of which were found to be elevated upon NINJ1 knockdown. Furthermore, we discovered that NINJ1 interacts with the xCT antiporter, which is responsible for cystine uptake for the biosynthesis of CoA and GSH. The removal of NINJ1 increased xCT levels and stability, enhancing cystine uptake and thereby providing protection against ferroptosis. Conversely, NINJ1 overexpression reduced xCT levels and sensitized ferroptosis. These findings reveal that NINJ1 regulates ferroptosis via a non-canonical mechanism, distinct from other regulated cell deaths.

Atopic dermatitis (AD) is a common chronic inflammatory skin disorder characterized by disrupted epidermal barrier function and aberrant immune responses. Despite recent developments in new therapeutics for AD, there is still a large unmet medical need for disease management due to the complex and multifactorial nature of AD. Recent genome-wide association studies (GWAS) have identified NLRP10 as a susceptible gene for AD but the physiological role of NLRP10 in skin homeostasis and AD remains unknown. Here we show that NLRP10 is downregulated in AD skin samples. Using an air-lift human skin equivalent culture, we demonstrate that NLRP10 promotes keratinocyte survival and is required for epidermal differentiation and barrier function. Mechanistically, NLRP10 limits cell death by preventing the recruitment of caspase-8 to the death inducing signaling complex (DISC) and by inhibiting its subsequent activation. NLRP10 also stabilizes p63, the master regulator of keratinocyte differentiation, to drive proper keratinocyte differentiation and to reinforce the barrier function. Our findings underscore NLRP10 as a key player in atopic dermatitis pathogenesis, highlighting NLRP10 as a potential target for therapeutic intervention to restore skin barrier function and homeostasis in AD.

Pancreatic ductal adenocarcinoma (PDAC) is a common malignant tumor of the digestive tract. Although gemcitabine and other therapeutic agents are effective in patients with advanced and metastatic pancreatic cancer, drug resistance has severely limited their use. However, the mechanisms of gemcitabine resistance in pancreatic cancer are poorly understood. In this study, ATAC-seq, ChIP-seq, and RNA-seq were performed to compare chromatin accessibility and gene expression in a patient-derived tumor xenograft (PDX) model of pancreatic cancer with or without gemcitabine resistance. Analyzing these sequencing data, we found a dramatic change in chromatin accessibility in the PDX model of gemcitabine-resistant tissues and identified a key gene, UBR7, which plays an important role in mediating gemcitabine resistance. Further research found that depletion of UBR7 significantly increased pancreatic carcinogenesis and the immunosuppressive microenvironment. Mechanistically, depleted UBR7 increased the stability of PRMT5, thereby promoting glycolysis in pancreatic cancer cells. Finally, an inhibitor that blocks PRMT5 (DS-437) significantly reduced gemcitabine resistance in pancreatic cancer caused by UBR7 depletion. In conclusion, our results illustrate that the UBR7-PRMT5 axis is a key metabolic regulator of PDAC and a promising target for the clinical treatment of gemcitabine resistance in PDAC.

MicroRNAs, including the tumor-suppressor miR-126 and the oncogene miR-221, regulate tumor formation and growth in colitis-associated cancer (CAC) and colorectal cancer (CRC). This study explores the impact of the epithelial cytokine heparin-binding epidermal growth factor (HB-EGF) and its receptor epidermal growth factor receptor (EGFR) on the pathogenesis of CAC and CRC, particularly in the regulation of microRNA-driven tumor growth and protease expression. In murine models of CRC and CAC, lack of miR-126 and elevated miR-221 expression in colonic tissues enhanced tumor formation and growth. MiR-126 downregulation in colon cells established a pro-tumorigenic proteolytic niche by targeting HB-EGF-active metalloproteinase-7, -9 (MMP7/MMP9), disintegrin, and metalloproteinase domain-containing protein 9, and modulating chemokine-mediated recruitment of HB-EGF-loaded inflammatory cells. Mechanistically, downregulation of HB-EGF and EGFR in the colon suppressed miR-221 and enhanced miR-126 expression via activating enhancer-binding protein 2 alpha. Reintroducing miR-126 reduced tumor development and HB-EGF expression. Combining miR-126 reintroduction, which targets specific HB-EGF-active proteases but not ADAM17, with MMP inhibitors like Batimastat or Marimastat effectively suppressed tumor growth. This combination normalized protease expression and balanced miR-126 and miR-221 levels in developing and growing tumors. These findings demonstrate that suppressing HB-EGF and EGFR1 shifts the balance from oncogenic miR-221 to tumor-suppressive miR-126 action. Consequently, normalizing miR-126 expression could open new avenues for treating patients with CAC and CRC, and this normalization is intertwined with the anticancer efficacy of MMP inhibitors.

P21 activated kinase 6 (PAK6) is a serine-threonine kinase with physiological expression enriched in the brain and overexpressed in a number of human tumors. While the role of PAK6 in cancer cells has been extensively investigated, the physiological function of the kinase in the context of brain cells is poorly understood. Our previous work uncovered a link between PAK6 and the Parkinson's disease (PD)-associated kinase LRRK2, with PAK6 controlling LRRK2 activity and subcellular localization via phosphorylation of 14-3-3 proteins. Here, to gain more insights into PAK6 physiological function, we performed protein-protein interaction arrays and identified a subgroup of PAK6 binders related to ciliogenesis. We confirmed that endogenous PAK6 localizes at both the centrosome and the cilium, and positively regulates ciliogenesis not only in tumor cells but also in neurons and astrocytes. Notably, PAK6 rescues ciliogenesis and centrosomal cohesion defects associated with the G2019S but not the R1441C LRRK2 PD mutation. Since PAK6 binds LRRK2 via its GTPase/Roc-COR domain and the R1441C mutation is located in the Roc domain, we used microscale thermophoresis and AlphaFold2-based computational analysis to demonstrate that PD mutations in LRRK2 affecting the Roc-COR structure substantially decrease PAK6 affinity, providing a rationale for the differential protective effect of PAK6 toward the distinct forms of mutant LRRK2. Altogether, our study discloses a novel role of PAK6 in ciliogenesis and points to PAK6 as the first LRRK2 modifier with PD mutation-specificity.

Venetoclax plus azacitidine treatment is clinically beneficial for elderly and unfit acute myeloid leukemia (AML) patients. However, the treatment is rarely curative, and relapse due to resistant disease eventually emerges. Since no current clinically feasible treatments are known to be effective at the state of acquired venetoclax resistance, this is becoming a major challenge in AML treatment. Studying venetoclax-resistant AML cell lines, we observed that venetoclax induced sublethal apoptotic signaling and DNA damage even though cell survival and growth were unaffected. This effect could be due to venetoclax inducing a sublethal degree of mitochondrial outer membrane permeabilization. Based on these results, we hypothesized that the sublethal apoptotic signaling induced by venetoclax could constitute a vulnerability in venetoclax-resistant AML cells. This was supported by screens with a broad collection of drugs, where we observed a synergistic effect between venetoclax and PARP inhibition in venetoclax-resistant cells. Additionally, the venetoclax-PARP inhibitor combination prevented the acquisition of venetoclax resistance in treatment naïve AML cell lines. Furthermore, the addition of azacitidine to the venetoclax-PARP inhibitor combination enhanced venetoclax induced DNA damage and exhibited exceptional sensitivity and long-term responses in the venetoclax-resistant AML cell lines and samples from AML patients that had clinically relapsed under venetoclax-azacitidine therapy. In conclusion, we mechanistically identify a new vulnerability in acquired venetoclax-resistant AML cells and identify PARP inhibition as a potential therapeutic approach to overcome acquired venetoclax resistance in AML.

Radiotherapy represents a major curative treatment for prostate cancer (PCa), but some patients will develop radioresistance (RR) and relapse. The underlying mechanisms remain poorly understood, and miRNAs might be key players in the acquisition and maintenance of RR. Through their encapsulation in small extracellular vesicles (EVs), they can also be relevant biomarkers of radiation response. Using next-generation sequencing, we found that miR-200c-3p was downregulated in PCa RR cells and in their small EVs due to a gain of methylation on its promoter during RR acquisition. We next showed that its exogenous overexpression restores the radiosensitivity of RR cells by delaying DNA repair through the targeting of HP1α. Interestingly, we also observed downregulation of miR-200c-3p expression by DNA methylation in radiation-resistant lung and breast cancer cell lines. In summary, our study demonstrates that the downregulation of miR-200c-3p expression in PCa cells and in their small EVs could help distinguish radioresistant from sensitive tumor cells. This miRNA targets HP1α to delay DNA repair and promote cell death.

Clear cell renal cell carcinoma (ccRCC) is characterized by Von Hippel Lindau (VHL) gene loss of function mutation, which leads to the accumulation of hypoxia-inducible factor 2α (HIF2α). HIF2α has been well-established as one of the major oncogenic drivers of ccRCC, however, its therapeutic targeting remains a challenge. Through an analysis of proteomic data from ccRCCs and adjacent non-tumor tissues, we herein revealed that Ubiquitin-Specific Peptidase 7 (USP7) was upregulated in tumor tissues, and its depletion by inhibitors or shRNAs caused significant suppression of tumor progression in vitro and in vivo. Mechanistically, USP7 expression is activated by the transcription factors FUBP1 and FUBP3, and it promotes tumor progression mainly by deubiquitinating and stabilizing HIF2α. Moreover, the combination of USP7 inhibitors and afatinib (an ERBB family inhibitor) coordinately induce cell death and tumor suppression. In mechanism, afatinib indirectly inhibits USP7 transcription and accelerates the degradation of HIF2α protein, and the combination of them caused a more profound suppression of HIF2α abundance. These findings reveal a FUBPs-USP7-HIF2α regulatory axis that underlies the progression of ccRCC and provides a rationale for therapeutic targeting of oncogenic HIF2α via combinational treatment of USP7 inhibitor and afatinib.