Cell Communication and Signaling最新文献

Vacuolar-type H+-ATPase (V-ATPase) is a crucial proton pump that plays an essential role in maintaining intracellular pH homeostasis and a variety of physiological processes. This review provides an in-depth exploration of the structural components, functional mechanisms, and regulatory modes of V-ATPase in cancer cells. Comprising two main domains, V₁ and V₀, V-ATPase drives the proton pump through ATP hydrolysis, sustaining the pH balance within the cell and organelles. In cancer cells, the enhanced activity of V-ATPase is closely associated with the proliferation and metastasis of tumor cells, and it promotes the growth and invasion of tumor cells by regulating pH values in the tumor microenvironment. Moreover, the interaction between V-ATPase and key metabolic regulatory factors, the mechanistic target of rapamycin complex 1 (mTORC1) and AMP-activated protein kinase (AMPK), impacts the metabolic state of cancer cells. The role of V-ATPase in tumor drug resistance and its regulatory mechanism in non-canonical autophagy offer new perspectives and potential targets for cancer therapy. Future research directions will focus on the specific mechanisms of action of V-ATPase in the tumor microenvironment and how to translate its inhibitors into clinical applications, providing significant scientific evidence for the development of new therapeutic strategies.

Chimeric antigen receptor T (CAR-T) cell therapy has shown remarkable success in hematologic malignancies but has encountered challenges in effectively treating solid tumors. One major obstacle is the presence of the immunosuppressive tumor microenvironment (TME), which is mainly built by myeloid-derived suppressor cells (MDSCs). Recent studies have shown that MDSCs have a detrimental effect on CAR-T cells due to their potent immunosuppressive capabilities. Targeting MDSCs has shown promising results to enhance CAR-T immunotherapy in preclinical solid tumor models. In this review, we first highlight that MDSCs increase tumor proliferation, transition, angiogenesis and encourage circulating tumor cells (CTCs) extravasation leading to tumor progression and metastasis. Moreover, we describe the main characteristics of the immunosuppressive activities of MDSCs on T cells in TME. Most importantly, we summarize targeting therapeutic strategies of MDSCs in CAR-T therapies against solid tumors. These strategies include (1) therapeutic targeting of MDSCs through small molecule inhibitors and large molecule antibodies; (2) CAR-T targeting cancer cell antigen combination with MDSC modulatory agents; (3) cytokine receptor antigen-targeted CAR-T indirectly or directly targeting MDSCs reshapes TME; (4) modified natural killer (NK) cells expressing activating receptor directly targeting MDSCs; and (5) CAR-T directly targeting MDSC selective antigens. In the near future, we are expected to witness the improvement of CAR-T cell therapies for solid tumors by targeting MDSCs in clinical practice.

Early dissemination refers to the process by which cancer cells spread to distant organs at an early stage of the disease, often before the primary tumor is clinically detectable. Experimental studies have demonstrated that Her2 promotes early dissemination of breast cancer by inhibiting the p38 signaling pathway. However, the precise mechanism by which Her2 suppresses the activation of p38 signaling in early-stage cancer cells (ECCs) remains unclear. Here, we report that MAP3K4, an upstream kinase of p38, is downregulated in Her2 + ductal carcinoma in situ (DCIS) cells and tissues, which is required for Her2-induced early dissemination of DCIS cells by regulating the activation of the p38 signaling cascade. Furthermore, Her2 suppresses the transcription of MAP3K4 by downregulating the expression of HOXB13, a crucial transcription factor contributing to MAP3K4 expression in DCIS cells. Together, these findings unveil a novel downstream regulatory mechanism through which Her2 inhibits the activation of p38 signaling and facilitates early dissemination of breast cancer, offering insights into the development of effective diagnostic methods and targeted therapies for inhibiting the early dissemination of Her2 + breast cancer.

Timely and accurate translation of maternal mRNA is essential for oocyte maturation and early embryonic development. Previous studies have highlighted the importance of Primordial Germ cell 7 (PGC7) as a maternal factor in maintaining DNA methylation of maternally imprinted loci in zygotes. However, it is still unknown whether PGC7 is involved in the regulation of Maternal mRNA Translation. In this study, we have identified that PGC7-AKT1-YBX1 axis is involved in promoting the translation of maternal mRNAs. PGC7 not only sustains AKT1 activity by counteracting PP2A dephosphorylation and facilitating PDK1-AKT1 binding but also assists AKT1 in phosphorylating the translation inhibitor YBX1. In the absence of PGC7, despite increased PIK3CA expression and AKT1 phosphorylation, AKT1 is unable to phosphorylate YBX1. PGC7 facilitates the interaction between AKT1 and YBX1, enhancing YBX1-Serine 100 phosphorylation, which leads to YBX1 dissociation from eIF4E, thereby activating the translation of maternal Cyclin B1 and YAP1. The findings demonstrate the indispensability of PGC7 for translation activation in mammalian oocytes and provide a potential network regulated by PGC7 in early oogenesis.

Cellular senescence is a phenomenon distinguished by the halting of cellular division, typically triggered by DNA injury or numerous stress-inducing factors. Cellular senescence is implicated in various pathological and physiological processes and is a hallmark of aging. The presence of accumulated senescent cells, whether transiently (acute senescence) or persistently (chronic senescence) plays a dual role in various conditions such as natural kidney aging and different kidney disorders. Elevations in senescent cells and senescence-associated secretory phenotype (SASP) levels correlate with decreased kidney function, kidney ailments, and age-related conditions. Strategies involving senotherapeutic agents like senolytics, senomorphics, and senoinflammation have been devised to specifically target senescent cells. Mesenchymal stem cells (MSCs) and their secreted factors may also offer alternative approaches for anti-senescence interventions. The MSC-derived secretome compromises significant therapeutic benefits in kidney diseases by facilitating tissue repair via anti-inflammatory, anti-fibrosis, anti-apoptotic, and pro-angiogenesis effects, thereby improving kidney function and mitigating disease progression. Moreover, by promoting the clearance of senescent cells or modulating their secretory profiles, MSCs could potentially reverse some age-related declines in kidney function.This review article intends to shed light on the present discoveries concerning the role of cellular senescence in kidney aging and diseases. Furthermore, it outlines the role of senotherapeutics utilized to alleviate kidney damage and aging. It also highlights the possible impact of MSCs secretome on mitigating kidney injury and prolonging lifespan across various models of kidney diseases as a novel senotherapy.

The primary cilium is a cellular organelle whose assembly and disassembly are closely linked to the cell cycle. The centriole distal appendage (DA) is essential for the early stages of ciliogenesis by anchoring the mother centriole to the cell surface. Despite the identification of over twelve proteins constituting the DA, including CEP83, CEP89, CEP164, FBF1, and SCLT1, their specific functions in ciliary dynamics are not fully understood. Here, we elucidate the precise role of DA proteins in ciliary assembly and disassembly. While Cep89 mutant cells exhibit normal ciliogenesis, the kinetics of ciliary disassembly is significantly delayed. Through siRNA-mediated knockdown of DA proteins, we identified two functional subgroups within DA proteins: CEP83, SCLT1, and CEP164, which are primarily essential for ciliary assembly and centriole docking, and CEP89 and FBF1, which specifically regulate ciliary disassembly. Notably, the depletion of CEP89 and FBF1 not only impedes ciliary disassembly but also disrupts the Aurora A kinase signaling pathway, leading to its downregulation and mislocalization at the basal body during serum-induced cell cycle re-entry. These findings suggest that DA components can be functionally categorized into two modules responsible for distinct aspects of ciliary dynamics, with broad implications for cellular signaling, homeostasis, and development.

Background: The innate immune system serves as the host's first line of defense against invading pathogens. Stimulator of interferon genes (STING) is a key component of this system, yet its relationship with glucose metabolism, particularly in antiviral immunity, remains underexplored.

Methods: Metabolomics analysis was used for detecting metabolic alterations in spleens from STING knockout (KO) and wild-type (WT) mice. Co-immunoprecipitation was employed for determining ubiquitination of TKT. Mass spectrometry was used for detecting interaction proteins of STING. Enzyme activity kits were used for detecting the activities of TKT and G6PD.

Results: In this study, we demonstrate that herpes simplex virus (HSV) infection activates the pentose phosphate pathway (PPP) in host cells, thereby initiating an antiviral immune response. Using STING-manipulated cells and systemic knockout mice, we show that STING positively regulates PPP, which, in turn, limits HSV infection. Inhibition of the PPP significantly reduced the production of antiviral immune factors and dampened STING-induced innate immune responses. Mechanistically, we discovered that STING interacts with transketolase (TKT), a key enzyme in the non-oxidative branch of the PPP, and reduces its ubiquitination via the E3 ubiquitin ligase UBE3A, stabilizing TKT. Silencing TKT or inhibiting its activity with oxythiamine diminished antiviral immune factor production.

Conclusion: Our findings reveal that the PPP plays a synergistic role in generating antiviral immune factors during viral infection and suggest that PPP activation could serve as an adjunct strategy for antiviral therapy.

Immune responses to tumors, comprising adaptive T cells and innate NK cells, arise very early in tumorigeneses and prior to detection of palpable tumors or before tissue pathology is evident. Yet, how nascent tumors evoke dendritic cell maturation and the resulting cytokine responses that are necessary for these effector anti-tumor immune responses is unknown. We have previously shown that CD91 expression on dendritic cells is important for immune surveillance, specifically for generating T cell and NK cell responses to nascent tumors. Here we show that engagement of CD91 by its ligands, the tumor-derived HSPs, triggers intracellular signaling within the dendritic cell and reprograms them to release cytokines and become receptive to other immune mediators. We identify AXL and Fgr as essential adaptor kinases that physically associate with, and phosphorylate, CD91 and are important for transmission of distinct but overlapping signaling in cells. Inhibition of these kinases prevents HSP-induced phosphorylation of signaling cascade components and downstream cytokine production. We show that two different immunogenic HSPs that bind CD91 differentially utilize AXL and Fgr and activate distinct programming of dendritic cells, which is important for the varied immunological responses that tumors evoke. Overall, these findings describe an innate sensing mechanism of nascent tumors by dendritic cells, resulting in initiation of anti-tumor responses via the HSP-CD91 axis.

Background: Advanced prostate cancer (PCa) often initially responds to androgen receptor signaling inhibitors (ARSI) but frequently develops resistance, driven by tumor heterogeneity and therapeutic pressure. Addressing the clinical challenge of identifying non-responsive patients and discovering new therapeutic targets is urgently needed.

Methods: We utilized single-sample gene set enrichment analysis (ssGSEA) to elucidate the influence of the GG-NER pathway on ARSI response in PCa. We then constructed and validated a prognostic model based on this pathway using LASSO regression, Kaplan-Meier analysis, Cox regression, and ROC analysis. Additionally, we mapped tumor mutations to delineate the mutational landscapes across different risk groups and explored functional pathways through GO, KEGG, and GSEA analyses. The impact of the GG-NER pathway on enzalutamide sensitivity and DNA repair in PCa was further validated through CCK-8 assays, colony formation assays, in vivo experiments, and immunofluorescence.

Results: ssGSEA indicated a trend of GG-NER pathway upregulation in patients with poor ARSI response. The GG-NER characteristic gene score (NECGS) identified a high-risk group with diminished ARSI response, serving as an independent prognostic indicator with strong predictive power. This high-risk group exhibited elevated TP53 mutation frequencies and significant enrichment in key pathways such as ribosome and mitochondrial functions, as well as MYC and E2F signaling. Experimental validation confirmed that targeting the GG-NER pathway or its key gene, ACTL6A, significantly reduces enzalutamide resistance in resistant cell lines and increases γH2AX expression.

Conclusion: NECGS effectively predicts ARSI response in PCa, and our comprehensive analysis underscores the critical role of the GG-NER pathway in enzalutamide resistance, positioning ACTL6A as a potential therapeutic target for PCa.

Background: Osteosarcoma (OSA), the most common primary bone malignancy, poses significant challenges due to its aggressive nature and propensity for metastasis, especially in adolescents. Mitophagy analysis can help identify new therapeutic targets and combined treatment strategies.

Methods: This study integrates single-cell sequencing (scRNA-seq) data and bulk-seq to identify mitophagy-related genes (MRGs) associated with the progression of OSA metastasis and analyze their clinical significance. scRNA-seq data elucidates the relationship between mitophagy and OSA metastasis, employing "CellChat" R package to explore intercellular communications and report on hundreds of ligand-receptor interactions. Subsequently, the combination of bulk-seq and CRISPR-Cas9 gene editing identifies mitophagy-related biomarker associated with metastatic prognosis. Finally, validation of the relationship between mitophagy and OSA metastasis is achieved through cellular biology experiments and animal studies.

Results: The distinct mitophagy activity of various mitochondria manifests in diverse spatial localization, cellular developmental trajectories, and intercellular interactions. OSA tissue exhibits notable heterogeneity in mitophagy within osteoblastic OSA cells. However, high mitophagy activity correlates consistently with high metastatic potential. Subsequently, we identified three critical genes associated with mitophagy in OSA, namely RPS27A, TOMM20 and UBB. According to the aforementioned queue of genes, we have constructed a mitophagy_score (MIP_score). We observed that it consistently predicts patient prognosis in both internal and external datasets, demonstrating strong robustness and stability. Furthermore, we have found that MIP_score can also guide chemotherapy, with varying sensitivities to chemotherapeutic agents based on different MIP_score. It is noteworthy that, through the integration of CRISPR-Cas9 genome-wide screening and validation via cellular and animal experiments, we have identified RPS27A as a potential novel biomarker for OSA.

Conclusions: Our comprehensive analysis elucidated the profile of mitophagy throughout the OSA metastasis process, forming the basis for a mitophagy-related prognostic model that addresses clinical outcomes and drug sensitivity following OSA metastasis. Additionally, an online interactive platform was established to assist clinicians in decision-making ( https://mip-score.shinyapps.io/labtan/ ). These findings lay the groundwork for developing targeted therapies aimed at improving the prognosis of OSA patients.