Cell Death & Disease最新文献

The transcription factor p63 is expressed in many different isoforms as a result of differential promoter use and splicing. Some of these isoforms have very specific physiological functions in the development and maintenance of epithelial tissues and surveillance of genetic integrity in oocytes. The ASPP family of proteins is involved in modulating the transcriptional activity of the p53 protein family members, including p63. In particular, iASPP plays an important role in the development and differentiation of epithelial tissues. Here we characterize the interaction of iASPP with p63 and show that it binds to the linker region between the DNA binding domain and the oligomerization domain. We further demonstrate that this binding site is removed in a splice variant of p63 where a stretch of five amino acids is replaced with a single alanine residue. This stretch contains a degenerate class II SH3 domain binding motif that is responsible for interaction with iASPP, as well as two positively charged amino acids. Moreover, the concomitant loss of the charged amino acids in the alternatively spliced version decreases the affinity of p63 to its cognate DNA element two- to threefold. mRNAs encoding full-length p63, as well as its alternatively spliced version, are present in all tissues that we investigated, albeit in differing ratios. We speculate that, through the formation of hetero-complexes of both isoforms, the affinity to DNA, as well as the interaction with iASPP, can be fine-tuned in a tissue-specific manner.

Doxorubicin, a representative drug of the anthracycline class, is widely used in cancer treatment. However, Doxorubicin-induced cardiotoxicity (DIC) presents a significant challenge in its clinical application. Mitochondrial dysfunction plays a central role in DIC, primarily through disrupting mitochondrial dynamics. This study aimed to investigate the impact of Rnd3 (a Rho family GTPase 3) on DIC, with a focus on mitochondrial dynamics. Cardiomyocyte-specific Rnd3 transgenic mice (Rnd3-Tg) and Rnd3^LSP/LSP mice (N-Tg) were established for in vivo experiments, and adenoviruses harboring Rnd3 (Ad-Rnd3) or negative control (Ad-Control) were injected in the myocardium for in vitro experiments. The DIC model was established using wild-type, N-Tg, and Rnd3-Tg mice, with subsequent intraperitoneal injection of Dox for 4 weeks. The molecular mechanism was explored through RNA sequencing, immunofluorescence staining, co-immunoprecipitation assay, and protein-protein docking. Dox administration induced significant mitochondrial injury and cardiac dysfunction, which was ameliorated by Rnd3 overexpression. Further, the augmentation of Rnd3 expression mitigated mitochondrial fragmentation which is mediated by dynamin-related protein 1 (Drp1), thereby ameliorating the PANoptosis (pyroptosis, apoptosis, and necroptosis) response induced by Dox. Mechanically, the interaction between Rnd3 and Rho-associated kinase 1 (Rock1) may impede Rock1-induced Drp1 phosphorylation at Ser616, thus inhibiting mitochondrial fission and dysfunction. Interestingly, Rock1 knockdown nullified the effects of Rnd3 on cardiomyocytes PANoptosis, as well as Dox-induced cardiac remodeling and dysfunction elicited by Rnd3. Rnd3 enhances cardiac resilience against DIC by stabilizing mitochondrial dynamics and reducing PANoptosis. Our findings suggest that the Rnd3/Rock1/Drp1 signaling pathway represents a novel target for mitigating DIC, and modulating Rnd3 expression could be a strategic approach to safeguarding cardiac function in patients undergoing Dox treatment. The graphical abstract illustrated the cardioprotective role of Rnd3 in DIC. Rnd3 directly binds to Rock1 in cytoplasm and ameliorates mitochondrial fission by inhibiting Drp1 phosphorylation at ser616, thereby alleviating PANoptosis (apoptosis, pyroptosis, and necroptosis) in DIC.

Aging of the brain vasculature plays a key role in the development of neurovascular and neurodegenerative diseases, thereby contributing to cognitive impairment. Among other factors, DNA damage strongly promotes cellular aging, however, the role of genomic instability in brain endothelial cells (EC) and its potential effect on brain homeostasis is still largely unclear. We here investigated how endothelial aging impacts blood-brain barrier (BBB) function by using excision repair cross complementation group 1 (ERCC1)-deficient human brain ECs and an EC-specific Ercc1 knock out (EC-KO) mouse model. In vitro, ERCC1-deficient brain ECs displayed increased senescence-associated secretory phenotype expression, reduced BBB integrity, and higher sprouting capacities due to an underlying dysregulation of the Dll4-Notch pathway. In line, EC-KO mice showed more P21⁺ cells, augmented expression of angiogenic markers, and a concomitant increase in the number of brain ECs and pericytes. Moreover, EC-KO mice displayed BBB leakage and enhanced cell adhesion molecule expression accompanied by peripheral immune cell infiltration into the brain. These findings were confined to the white matter, suggesting a regional susceptibility. Collectively, our results underline the role of endothelial aging as a driver of impaired BBB function, endothelial sprouting, and increased immune cell migration into the brain, thereby contributing to impaired brain homeostasis as observed during the aging process.

Asparagine endopeptidase (AEP) is ubiquitously expressed in both physiological and pathological contexts, yet its precise role and functional mechanism in breast cancer remain elusive. Here, we identified increased AEP expression in breast cancer tissues, which correlated with poorer survival rates and a propensity for lung metastasis among breast cancer patients. Loss of AEP impaired colony formation by breast cancer cells in vitro and suppressed lung metastasis in mice. By Gene Set Enrichment Analysis (GSEA) analysis, we uncovered a positive association between aberrant AEP expression and autophagy as well as lysosomal function. Loss of AEP in breast cancer cells led to reduced autophagosome clearance and impaired lysosomal degradation. Mechanically, by co-immunoprecipitation and in vitro enzymatic cleavage assays, we identified the regulatory subunit p85 of class IA PI3K phosphatidylinositol 3-kinase (PI3K), as a substrate of AEP. Loss of AEP led to elevated endo/lysosomal PI3K activity and subsequent conversion of PtdIns(4,5)P2 (PIP2) to PtdIns(3,4,5)P3 (PIP3) on endo/lysosome membranes. Notably, the novel function of endo/lysosomal PI3K which was differently with its role in cytomembrane, was revealed by pharmacological inhibition with a potent endo/lysosomal PI3K inhibitor PIK75. PIK75 treatment showed increased vacuolar-ATPase assembly endo/lysosome membranes, prevented over lysosome perinuclear clustering/fusion and enhanced autophagosome clearance. Our findings demonstrate that AEP regulates cellular autophagy by modulating lysosomal function through its control over endo/lysosomal PI3K activity. These results suggest that AEP may serve as a potential target for suppressing metabolic adaptations in cancer.

The influence of the mitochondrial control system on ischemic heart disease has become a major focus of current research. Mitophagy, as a very crucial part of the mitochondrial control system, plays a special role in ischemic heart disease, unlike mitochondrial dynamics. The published reviews have not explored in detail the unique function of mitophagy in ischemic heart disease, therefore, the aim of this paper is to summarize how mitophagy regulates the progression of ischemic heart disease. We conclude that mitophagy affects ischemic heart disease by promoting cardiomyocyte hypertrophy and fibrosis, the progression of oxidative stress, the development of inflammation, and cardiomyocyte death, and that the specific mechanisms of mitophagy are worthy of further investigation.

Radiotherapy resistance is one of the main reasons for the dismal clinical outcome of patients with esophageal squamous cell carcinoma (ESCC). Therefore, clarifying the targets and molecular mechanisms of radiotherapy resistance in ESCC is of great theoretical and clinical significance to enhance the efficacy of radiotherapy. In this study, GPR37 was identified as a key factor facilitating ESCC radiosensitization. We found that GPR37 is lowly expressed in ESCC, especially in radioresistant ESCC tumors. And its insufficiency is related to the malignant characteristics and unfavorable prognosis in ESCC. Further investigation revealed that GPR37 level is inversely regulated by promoter methylation but positively regulated by ZNF750. Functionally, GPR37 could not only overcome radioresistance of ESCC, but also inhibit proliferation, migration, and invasion. Mechanistically, GPR37 interacts with the ATP1A1 protein, effectively promoting its ubiquitination-induced degradation, thereby limiting the activation of the AKT/mTOR signaling pathway. Additionally, GPR37 can be transported to recipient cells via exosomes and inhibit the malignant behavior of recipient cells. Overall, these findings suggest that GPR37-ATP1A1 axis holds potential as a therapeutic target for the management of ESCC, especially for overcoming radiation resistance.

Pancreatic cancer (PC) is one of the most lethal malignant tumors that lacks effective treatment, and gemcitabine-based chemoresistance occurs frequently. Therefore, new therapeutic strategies for PC are urgently needed. Tripartite motif containing 59 (TRIM59) plays an important role in breast and lung cancer chemoresistance. However, the association between TRIM59 and gemcitabine resistance in PC remains unclear. We identified TRIM59 as an innovative E3 ubiquitin ligase that activated Notch signaling in PC. TRIM59 levels were increased in PC and positively correlated with poor prognosis and gemcitabine resistance in PC patients. TRIM59 facilitated gemcitabine resistance in PC cells in vitro and in vivo. TRIM59 interacted with recombination signal binding protein for immunoglobulin kappa J region (RBPJ) and stabilized it by promoting K63-linked ubiquitination. RBPJ transcriptionally upregulated TRIM59 expression, forming a positive feedback loop with TRIM59. We identified a novel TRIM59 inhibitor, catechin, and confirmed that it sensitized PC cells to gemcitabine. TRIM59 conferred gemcitabine resistance in PC by promoting RBPJ K63-linked ubiquitination, followed by activating Notch signaling. Therefore, our study provides a promising target for gemcitabine sensitization in PC treatment.

Cisplatin (CDDP) resistance has been established to significantly impact Bladder Cancer (BCa) therapy. On the other hand, the crucial regulatory involvement of SIRT7 and EZH2 in bladder cancer development is well known. Herein, the collaborative regulatory roles and underlying mechanisms of SIRT7 and EZH2 in CDDP resistance in bladder cancer were explored. Immunohistochemistry (IHC) and Western Blot (WB) analyses were used to assess the expression levels of SIRT7/EZH2 and RND3 in bladder cancer tissues, normal ureteral epithelial cells, and bladder cancer cell lines. Furthermore, the impact of various treatments on of UMUC3 cell proliferation and CDDP sensitivity was assessed using CCK-8 assays, plate cloning assays, and flow cytometry analysis. Additionally, the levels of H3K18ac and H3K27me³ at the promoter region of the RND3 gene, the binding abilities of SIRT7 and EZH2, and the succinylation level of the EZH2 protein were examined using ChIP-qPCR assays, CO-IP assays, and IP assays, respectively. Moreover, in vivo experiments were conducted using a bladder cancer mouse model created by subcutaneously injecting UMUC3 cells into Balb/c nude mice. According to the results, SIRT7 correlated with the sensitivity of bladder cancer cells to both the platinum-based chemotherapy and CDDP. Specifically, SIRT7 could bind to the RND3 promoter, downregulating H3K18ac and RND3, ultimately leading to an increased CDDP sensitivity in UMUC3 cells. Furthermore, EZH2 siRNA could decrease H3K27me³ levels in the RND3 promoter, upregulating RND3. Overall, in the promoter region of the RND3 gene, SIRT7 upregulated H3K27me³ and EZH2 downregulated H3K18ac, leading to a decline in RND3 expression and CDDP sensitivity in bladder cancer cells. Additionally, SIRT7 reduced the succinylation of the EZH2 protein resulting in an EZH2-mediated RND3 downregulation. Therefore, targeting SIRT7 and EZH2 could be a viable approach to enhancing CDDP efficacy in bladder cancer treatment.

Ovarian cancer (OC) is prone to adipose tissue metastasis. However, the underlying molecular mechanisms remain elusive. Here, we observed that omental adipocytes were induced into cancer-associated adipocytes (CAAs) by OC-derived TGF-β1 to establish a pre-metastatic niche (PMN) through collagen and fibronectin secretion. Mechanistically, OC-derived TGF-β1 binds to adipocyte membrane receptors and thus activates intracellular signaling by SMAD3 phosphorylation. The activation of TGF-β1/SMAD3 signaling pathway dedifferentiates adipocytes into CAAs by upregulating Tribbles homolog 3 (TRIB3), which suppresses the phosphorylation of CEBPβ. Additionally, CAAs secrete collagen I, collagen VI, and fibronectin to remodel the extracellular matrix and promote the adhesion of OC cells. Pharmacological inhibition of the TGF-β1/SMAD3 pathway significantly inhibits CAAs and PMN formation, thereby reducing the OC metastatic burden. Our findings indicate that the formation of CAAs and PMN in adipose tissues facilitates OC cell implantation and blocking the TGF-β1/SMAD3 signaling pathway could prevent OC omental metastasis.