Huo X, Wang Y, Wang Z
… +9 more, Huang L, Mi R, Ji B, Chen Y, Yang Y, Wang J, Han L, Liu R, Jiang Z
Biochim Biophys Acta Mol Cell Res
· 2026 Jun · PMID 42218966
·
Publisher ↗
Premature Ovarian Insufficiency (POI) is characterized by declining ovarian function before the age of 40, which affects female fertility. Granulosa cells (GCs) are essential for follicular development and ovarian functi...Premature Ovarian Insufficiency (POI) is characterized by declining ovarian function before the age of 40, which affects female fertility. Granulosa cells (GCs) are essential for follicular development and ovarian function, and their dysfunction is closely involved in the pathogenesis of POI. In this study, transcriptomic data of GCs from POI patients and controls were analyzed using weighted Gene Co-expression Network Analysis (WGCNA), differential expressed analysis, Protein-Protein Interaction (PPI) network, and receiver operating characteristic (ROC) analysis to identify key genes associated with POI. A cisplatin-induced POI-like rat model was established for in vivo validation and mechanistic exploration. In vitro, human GCs were treated with cisplatin plus the ferroptosis inhibitor deferoxamine (DFO), cisplatin plus small interfering RNA. Overexpression lentiviral model was used to further assess the role of candidate gene in ferroptosis. We found that 7-dehydrocholesterol reductase (DHCR7) as a key gene associated with POI. In the cisplatin-induced POI-like rat model, DHCR7 expression was significantly upregulated and was accompanied by enhanced ferroptosis and decreased GCs proliferation. Similarly, in human GCs, cisplatin treatment enhanced DHCR7 expression and promoted ferroptosis. DFO treatment or DHCR7 knockdown attenuated ferroptosis and rescued the survival of GCs. In contrast, DHCR7 overexpression aggravated ferroptosis. This study suggests that DHCR7 promotes GCs ferroptosis and participates in the pathogenesis of POI, indicating that DHCR7 may represent a potential therapeutic target for POI.
The Janus kinase (JAK)/STAT signaling pathway plays a pivotal role in cancer biology as well as in inflammatory and autoimmune disorders such as psoriasis. Recent advances in biomedical research and targeted therapies ha...The Janus kinase (JAK)/STAT signaling pathway plays a pivotal role in cancer biology as well as in inflammatory and autoimmune disorders such as psoriasis. Recent advances in biomedical research and targeted therapies have highlighted the importance of computational approaches for accelerating the discovery of selective kinase inhibitors. This study aimed to develop a robust computational framework for predicting the inhibitory potency of JAK2 ligands and for analyzing their binding interactions using structure-based methods. A curated dataset of 1869 chemically valid JAK2 ligands with experimentally reported K values was compiled, standardized, and converted to pK. Using this dataset, a bond-aware graph neural network (GNN) was trained and evaluated for pK prediction. Top-ranked predicted ligands were further examined via molecular docking, pharmacophore modeling, and molecular dynamics simulations to assess their interactions within the JAK2 ATP-binding site. The proposed model achieved strong predictive performance, yielding an average test-set R of 0.91 ± 0.01, MAE of 0.14 ± 0.01, and RMSE of 0.26 ± 0.02 across repeated data splits. Structure-based analyses supported the predicted binding poses and identified key stabilizing interactions within the JAK2 ATP-binding site. Overall, this integrative computational framework provides a reliable approach for predicting JAK2 inhibitory potency and offers mechanistic insights that may support the computational prioritization of candidate molecules for future experimental evaluation.
Regulation of proton motive force (pmf) via ATP synthase activity is a critical mechanism by which photosynthetic organisms maintain redox homeostasis and control the activation and inactivation of photoprotective respon...Regulation of proton motive force (pmf) via ATP synthase activity is a critical mechanism by which photosynthetic organisms maintain redox homeostasis and control the activation and inactivation of photoprotective responses under fluctuating light conditions. Here, we used time-resolved electrochromic shift measurements to investigate pmf dynamics in the C model plant Arabidopsis thaliana and the C model grass Setaria viridis. Our results reveal that ATP synthase is dynamically regulated during light fluctuations, but in Arabidopsis this regulation could not be explained by the established light-induced reduction of the CF₁γ subunit by thioredoxins, suggesting alternative control mechanisms. The PROTON GRADIENT REGULATION 5 (PGR5) protein, previously proposed to facilitate cyclic electron transport (CET) in plants and algae, also has a potential role in regulation of ATP synthase. We therefore investigated pmf dynamics, cytochrome f redox changes, and linear and cyclic PSI electron transport rates in WT and pgr5 knock-out mutants and revealed that while PGR5 was not required for CET, it was needed for downregulating ATP synthase under high irradiance in both species. Furthermore, in Arabidopsis disturbance of thiol redox regulation by addition of N-ethylmaleimide resulted in downregulation of ATP synthase conductivity in WT but not in pgr5 mutants, and PGR5 interacted with CF₁γ in planta. We suggest that PGR5 functions as a conserved thiol redox state dependent inhibitor of chloroplast ATP synthase under high light, contributing to pmf retention and photoprotection.
Dysregulated lipid metabolism drives atherosclerosis (AS). Yacon, an Andean lipid-modulating tuber, exerts anti-AS potential, but mechanisms remain unclear. We integrated network pharmacology, machine learning, single-ce...Dysregulated lipid metabolism drives atherosclerosis (AS). Yacon, an Andean lipid-modulating tuber, exerts anti-AS potential, but mechanisms remain unclear. We integrated network pharmacology, machine learning, single-cell RNA sequencing (scRNA-seq), and in vivo validation to explore its anti-AS effects and targets. Active constituents and targets were curated from literature, TCMSP, and SwissTargetPrediction; lipid/AS genes from GeneCards, OMIM, and GEO were filtered via limma, WGCNA, LASSO, randomForest, and SVM-RFE. Immune infiltration and external validation confirmed hub gene relevance. scRNA-seq prioritized FABP5; docking and dynamics quantified compound-FABP5 interactions. In vivo efficacy was tested in high-fat diet (HFD)-fed ApoE-/- mice via histology (Oil Red O, H&E, and Masson) and molecular assays (RT-qPCR, Western blot, and immunofluorescence). We identified 12 constituents, 384 targets, and seven core targets (AURKA, MMP9, FABP5, etc.), with FABP5 top-ranked. Docking and dynamics identified Enhydrin as the strongest FABP5 binder. Enhydrin administration was associated with reduced hepatic lipid accumulation, decreased serum triacylglycerol (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels, and increased high-density lipoprotein cholesterol (HDLC) levels. Histopathological analysis of arterial tissues revealed attenuated vascular lipid deposition and delayed atherosclerotic lesion progression. Across assays, Enhydrin downregulated FABP5, reduced abnormal fatty acid trafficking, and upregulated PPARγ and ABCA1, with markedly reduced vascular lipid deposition and improved serum lipid profiles, reflecting enhanced cholesterol efflux. Conclusion: Our integrative multi-omics analysis pinpointed FABP5 as a promising novel target for yacon-derived Enhydrin in atherosclerosis. In vivo, Enhydrin markedly downregulated FABP5 and upregulated PPARγ and ABCA1, suggesting this axis mediates its anti-atherosclerotic activity. SIGNIFICANCE STATEMENT: 1: This study identified FABP5 as a candidate target for atherosclerosis through integrative multi-omics, and its association with the anti-atherosclerotic effects of Enhydrin suggests therapeutic potential. 2: The anti-atherosclerotic effects of yacon's active components and their underlying molecular pathways were systematically screened and preliminarily characterized by integrating bioinformatic prediction with in vivo validation, laying a preliminary theoretical foundation for further pharmacological investigation and clinical translation.
Siegfried G, Liu Y, He Z
… +5 more, Evrard S, Badiola I, Pernot S, Creemers JWM, Khatib AM
Biochim Biophys Acta Rev Cancer
· 2026 May · PMID 42214771
·
Publisher ↗
Increasing efforts have focused on identifying vulnerabilities within the signaling networks of KRAS that sustain its oncogenic activity. Recently, Furin-like enzymes or proprotein convertase, proteases responsible for t...Increasing efforts have focused on identifying vulnerabilities within the signaling networks of KRAS that sustain its oncogenic activity. Recently, Furin-like enzymes or proprotein convertase, proteases responsible for the activation of various signaling molecules, have emerged as key regulators. Furin, modulate KRAS-related signaling by processing growth factors, cytokines, and receptor tyrosine kinases (RTKs). Repression of Furin selectively impairs the proliferation and survival of KRAS-mutant colorectal cancer cells compared with wild-type KRAS cells. Furin inhibition disrupts various RTK maturation, attenuates downstream signaling, and remodels the tumour microenvironment toward an immune-stimulatory phenotype. Furin inhibition also repress KRAS-mutant-mediated resistance by blocking the maturation of multiple escape pathways, including compensatory RTK activation. This review summarizes current evidence on the crosstalk between KRAS signaling and Furin-like enzymes, emphasizing their cooperative roles in tumour progression and immune escape. Targeting protein maturation by these enzymes may therefore represent a therapeutic approach for KRAS-mutant colorectal cancer, offering new opportunities for personalized treatment.
Pastwińska J, Karwaciak I, Karaś K
… +2 more, Sałkowska A, Ratajewski M
Biochim Biophys Acta Rev Cancer
· 2026 May · PMID 42214769
·
Publisher ↗
Immune checkpoint inhibitor (ICI)-based combinations have reshaped systemic therapy for unresectable hepatocellular carcinoma (HCC), yet durable responses remain limited, underscoring the need for mechanism-driven partne...Immune checkpoint inhibitor (ICI)-based combinations have reshaped systemic therapy for unresectable hepatocellular carcinoma (HCC), yet durable responses remain limited, underscoring the need for mechanism-driven partners that reprogram the cirrhosis-conditioned tumor microenvironment. Here, we synthesize evidence supporting IL-17 family signaling as such a tractable axis and emphasize three translational takeaways. First, "IL-17 blockade" is not a single intervention: canonical IL-17A/F signaling through IL-17RA/RC differs from non-canonical nodes, including IL-17C signaling via IL-17RA/IL-17RE and the dual-ligand IL-17RB node (IL-25 versus IL-17B), which can yield context-dependent-and potentially opposing-effects. Second, HCC-focused models implicate an IL-17A-STAT3-PD-L1 immune-evasion circuit and show that IL-17A neutralization can enhance the activity of PD-1/PD-L1 blockade, positioning IL-17A/F inhibition primarily as an ICI-sensitizing strategy. Third, we argue that clinical translation should prioritize biomarker-guided, etiology-aware early-phase studies with on-treatment pharmacodynamic readouts, rather than unselected monotherapy, while explicitly accounting for infection and gut-barrier risks in cirrhosis.
Hu Y, Yu P, Yan Z
… +5 more, Chen C, Zhao Y, Lv Y, Zhong J, Qian X
Biochim Biophys Acta Mol Cell Res
· 2026 May · PMID 42214628
·
Publisher ↗
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, and angiogenesis is a critical driver of tumor growth and metastasis. In this study, we found that FMR1, an RNA-binding protein, was...Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, and angiogenesis is a critical driver of tumor growth and metastasis. In this study, we found that FMR1, an RNA-binding protein, was markedly upregulated in CRC tissues and was positively associated with microvessel density (MVD), CD34 expression, and VEGFA levels. Functional experiments, including HUVEC tube formation and chick chorioallantoic membrane (CAM) assays, showed that FMR1 overexpression promoted angiogenesis, whereas FMR1 knockdown suppressed this process. Mechanistically, FMR1 enhanced VEGFA expression and secretion, thereby activating MAPK and PI3K signaling pathways in endothelial cells and promoting their proliferation and tube formation. Notably, VEGFA silencing attenuated the pro-angiogenic effects induced by FMR1. In addition, we identified RREB1 as an upstream transcriptional activator of FMR1. ChIP-qPCR and luciferase reporter assays demonstrated that RREB1 directly binds to the FMR1 promoter, and RREB1 expression was positively correlated with FMR1 levels in CRC tissues. Collectively, these findings reveal a previously unrecognized RREB1-FMR1-VEGFA signaling axis that promotes angiogenesis in CRC, highlighting its potential as a prognostic biomarker and therapeutic target.
The ESCRT (Endosomal Sorting Complexes Required for Transport) pathway is a conserved cellular machinery essential for reverse-topology membrane fission events, such as multivesicular body biogenesis and cytokinesis. Hum...The ESCRT (Endosomal Sorting Complexes Required for Transport) pathway is a conserved cellular machinery essential for reverse-topology membrane fission events, such as multivesicular body biogenesis and cytokinesis. Human Immunodeficiency Virus Type 1 (HIV-1) co-opts this machinery to mediate the final scission step of virion budding from the host cell membrane. This review presents our current understanding of how HIV-1 hijacks the ESCRT system, moving beyond a simple recruitment model to a dynamic interplay with host cell regulation. We explore the spatial organization of the budding machinery at nanoscale domains, the layered control systems governing ESCRT activity, including molecular switches, post-translational modifications, and host restriction factors, and the integration of viral budding with cellular signaling networks. A key emerging theme is the plasticity of the viral budding program, where redundant recruitment pathways and adaptive sequence variations allow HIV-1 to maintain release across diverse cell types and under immune pressure. Finally, we discuss the translational implications of these insights, evaluating the ESCRT pathway as a source of potential therapeutic targets and outlining the challenges and future directions for exploiting this essential host-virus interface.
Biochim Biophys Acta Rev Cancer
· 2026 May · PMID 42208920
·
Publisher ↗
Cancer is a major global cause of mortality, underscoring the urgent need to decode its fundamental biology and advance targeted therapeutic strategies. The Hippo pathway, a highly conserved signaling cascade, plays indi...Cancer is a major global cause of mortality, underscoring the urgent need to decode its fundamental biology and advance targeted therapeutic strategies. The Hippo pathway, a highly conserved signaling cascade, plays indispensable roles in regulating organ size, suppressing tumorigenesis and sustaining stem cell self-renewal. Within tumors, a subpopulation of cancer stem cells (CSCs) possesses the dual capacity for self-renewal and differentiate, thereby driving tumor growth and heterogeneity. Notably, CSC-like cells can be produced by the aberrant activation of epithelial-mesenchymal transition (EMT), a de-differentiation program promoting tumor progression. Emerging evidence indicates that dysregulation of Hippo pathway signaling leads to tumor progression by enhancing CSC characteristics and facilitating EMT. The Hippo pathway also has tissue specific regulatory patterns and plays context dependent dual roles in the tumor microenvironment, either as a tumor suppressor or as an oncogenic driver. Whereas early-stage clinical trials targeting the Hippo pathway have both confirmed the therapeutic potential and revealed major challenges associated with on-target specificity and safety. This review synthesizes recent breakthroughs in our understanding of the mechanistic links between Hippo signaling, CSCs and tumor progression, offering novel perspectives on potential therapeutic vulnerabilities.
Biochim Biophys Acta Rev Cancer
· 2026 May · PMID 42208919
·
Publisher ↗
Tumor heterogeneity is a fundamental feature of malignant tumors and a major driver of treatment resistance, ultimately contributing to treatment resistance, therapeutic failure, disease recurrence, and poor outcome. Rat...Tumor heterogeneity is a fundamental feature of malignant tumors and a major driver of treatment resistance, ultimately contributing to treatment resistance, therapeutic failure, disease recurrence, and poor outcome. Rather than being static, heterogeneity arises early during tumorigenesis and continues to evolve during progression, metastasis, and therapeutic selection. Advances in single-cell and spatial omics, integrative multi-omics profiling, liquid biopsy, and computational modeling have markedly improved the characterization of heterogeneity across genetic, epigenetic, transcriptomic, phenotypic, and microenvironmental dimensions. However, translating heterogeneity profiling into routine clinical decision-making remains challenging due to sampling bias, technical variability, data-integration complexity, and the need for prospectively validated, actionable metrics. In this review, we summarize the biological origins and major classifications of tumor heterogeneity, discuss current approaches for its detection and longitudinal monitoring, examine its implications for established and emerging therapies, and highlight precision-oncology strategies aimed at anticipating, tracking, and ultimately exploiting heterogeneity to achieve durable cancer control.
Biochim Biophys Acta Rev Cancer
· 2026 May · PMID 42208918
·
Publisher ↗
Most deaths from pancreatic ductal adenocarcinoma (PDAC) result from metastatic organ failure rather than primary tumor burden. Across the metastatic cascade, tumor cells encounter hypoxia, nutrient limitation, oxidative...Most deaths from pancreatic ductal adenocarcinoma (PDAC) result from metastatic organ failure rather than primary tumor burden. Across the metastatic cascade, tumor cells encounter hypoxia, nutrient limitation, oxidative stress, immune pressure, and changing stromal conditions, and only those capable of dynamic metabolic adaptation successfully disseminate and colonize distant sites. In this review, we summarize how metabolic plasticity shapes PDAC dissemination, organ-specific colonization, and metastatic outgrowth. We further discuss how this framework may shift therapeutic strategy from broad metabolic blockade toward precision interventions that target metastatic fitness.
Biochim Biophys Acta Rev Cancer
· 2026 May · PMID 42208917
·
Publisher ↗
Liver metastasis is an intractable clinical challenge due to profound immunosuppression within the liver metastatic niche (LMN), which fundamentally limits immunotherapy efficacy. The unique immune landscape of LMN is sh...Liver metastasis is an intractable clinical challenge due to profound immunosuppression within the liver metastatic niche (LMN), which fundamentally limits immunotherapy efficacy. The unique immune landscape of LMN is shaped by inter-organ, primary tumor-origin, and intra-lesional heterogeneity, driven by multilayered mechanisms including poor immunogenicity, antigen presentation deficiency, antitumor immune cell dysfunction, hyperactive immunosuppressive cells, spatial immune remodeling and host systemic factors. Temporally, LMN evolves from immune surveillance to immune escape. Notably, distinct primary tumors share certain common LMN features, enabling a potential paradigm shift from primary tumor-based classification to LMN-guided subtyping. Precision strategies integrating multi-omics, dynamic biomarkers, and combinatorial interventions hold promise to overcome LMN-driven resistance. This review delineates the spatiotemporal immune remodeling of the LMN, summarizes current therapeutic strategies, and highlights future translational priorities for precision immunotherapy.
Endothelial cells (EC) form the inner lining of the blood vessels and are essential for the vascular homeostasis. EC death has been implicated in the pathology of vascular diseases. Our previous studies indicated that do...Endothelial cells (EC) form the inner lining of the blood vessels and are essential for the vascular homeostasis. EC death has been implicated in the pathology of vascular diseases. Our previous studies indicated that docosahexaenoic acid (DHA) induces EA.hy926 EC death by upregulating lipid droplet (LD) biogenesis and activating p38 MAPK, however, how LDs contribute to this process remains unclear. DHA belongs to the polyunsaturated fatty acids that are susceptible to lipid peroxidation, which is a common mechanism in lipid-induced cell injury and ferroptosis. Therefore, the current study is to investigate the mechanism of LD in the regulation of lipid peroxidation in relation to p38 MAPK in DHA-induced EA.hy926 endothelial ferroptosis. Results showed that DHA induced a time-dependent, bidirectional modulation of GPX4 expression accompanied by a progressive GSH and NADPH depletion and increased lipid peroxidation in ECs. Suppression of LD formation through diacylglycerol acyltransferases inhibition, siRNA, or promotion of LD lipolysis reduced lipid peroxidation and restored the GPX4 expression. Inhibiting lipid peroxidation chemically, activating GPX4 or supplementing GSH all prevented the cell death by DHA. Our findings reveal a novel role of LD in regulating GPX4-mediated lipid peroxidation and highlight the key role of p38 MAPK in downregulating GPX4 in lipid peroxidation-induced EC ferroptosis by DHA. In conclusion, the present study suggested that DHA-induced LD formation in ECs increases the membrane area, which could facilitate the lipid peroxidation reaction, disrupt the endogenous GPX4 antioxidant system, and thereby exacerbate the detrimental effects of lipid peroxidation, ultimately leading to cell ferroptosis.
PPARα plays a pivotal role in regulating hepatic fatty acid oxidation and activation of PPARα has been well known to stimulate mitochondrial β-oxidation and has the potential to reduce hepatic lipid level, while evidence...PPARα plays a pivotal role in regulating hepatic fatty acid oxidation and activation of PPARα has been well known to stimulate mitochondrial β-oxidation and has the potential to reduce hepatic lipid level, while evidences indicate that administration of PPARα agonist does not affect hepatic triglyceride level. Therefore, an alternative mechanism might work to counteract the lipid-lowering effect of PPARα agonist. As fatty acids can also be metabolized in peroxisome and the acetyl-CoA generated in peroxisomal β-oxidation could be used for the biosynthesis of malonyl-CoA, a critical molecule in controlling mitochondria fatty acid oxidation. We hypothesize that peroxisomal β-oxidation might play a role in regulating mitochondrial fatty acid oxidation through mediating malonyl-CoA formation. This study demonstrates a counteracting mechanism by which induction of peroxisomal β-oxidation causes suppression of mitochondrial fatty acid oxidation in animals administered with PPARα agonist. PPARα agonist induces oxidation of fatty acids by peroxisomes and generates considerable acetate in the liver, which significantly elevates hepatic content of malonyl-CoA, and causes suppression of mitochondrial β-oxidation. Specific inhibition of peroxisomal β-oxidation enhances mitochondrial fatty acid oxidation and attenuates hepatic lipid accumulation by reducing acetate and malonyl-CoA formation in the mice treated with PPARα agonist. It is suggested that combination therapy of PPARα agonist and peroxisomal β-oxidation inhibitor might be a novel and effective treatment of fatty liver and related metabolic disorder through maximization of mitochondrial fatty acid oxidation.
Biochim Biophys Acta Mol Cell Res
· 2026 Jun · PMID 42203132
·
Publisher ↗
Breast cancer continues to pose a significant health threat to women globally, highlighting the urgent need for novel therapeutic targets. The Wnt/β-catenin pathway plays an important role in tissue homeostasis. The Wnt/...Breast cancer continues to pose a significant health threat to women globally, highlighting the urgent need for novel therapeutic targets. The Wnt/β-catenin pathway plays an important role in tissue homeostasis. The Wnt/β-catenin signaling pathway frequently contributes to serious diseases, particularly cancer, through its dysregulation [1]. Transmembrane protein 132A (TMEM132A) serves as a potential regulator of the canonical Wnt pathway and is related to cancer progression. Nevertheless, the function of TMEM132A in breast cancer remains inadequately verified (Gao et al., 2023) [2]. In the present work, we initially confirmed the substantial overexpression of TMEM132A in breast cancer by analyzing TCGA, GEO, and GTEx datasets. This finding was further validated in breast cancer cell lines, where its expression correlated with unfavorable prognosis. TMEM132A overexpression was found to augment proliferation, migration, and invasion, and inhibit apoptosis in breast cancer cell lines (MDA-MB-231 and MCF-7), as demonstrated through functional validation, while its knockdown induced opposite effects. Mechanistically, TMEM132A knockdown reduced the expression of key Wnt pathway components, including Wnt3a, β-catenin, c-Myc, and Cyclin D1. Notably, nuclear and cytoplasmic fractionation assays demonstrated that TMEM132A promotes the nuclear accumulation of β-catenin, indicating enhanced activation of Wnt/β-catenin signaling. Furthermore, treatment with the Wnt inhibitor C59 attenuated the tumor-promoting effects induced by TMEM132A overexpression. Our findings establish that TMEM132A is a critical regulator of this signaling axis in cancer progression, highlighting its potential as a therapeutic target for breast cancer.
Benedetti R, Amato RP, Di Crosta M
… +5 more, Gilardini Montani MS, Santarelli R, Gonnella R, D'Orazi G, Cirone M
Biochim Biophys Acta Mol Cell Res
· 2026 Jun · PMID 42203131
·
Publisher ↗
Post-translational modifications (PTMs) play a key role in regulating protein/protein interactions and protein stability, thus influencing protein expression and function. HSPs and p53, including its wtp53 and mutp53 for...Post-translational modifications (PTMs) play a key role in regulating protein/protein interactions and protein stability, thus influencing protein expression and function. HSPs and p53, including its wtp53 and mutp53 forms, make no exception to this rule, although the impact of PTMs on the regulation of these proteins has not yet been fully elucidated, particularly in the case of mutp53. These proteins, unlike wtp53, can behave as oncogenes, making their targeting an important step for successful anticancer therapy. We previously reported that mutp53 is degraded, preferentially via CMA, in colon cancer cells stressed by long-term TG treatment. Whether TG could induce PTMs and how they could contribute to mutp53 degradation has not yet been investigated and will be explored in this study. Acetylation of mutp53, as well as HSP90, has been reported to promote mutp53 degradation. However, we found that TG promoted deacetylation of mutp53 and HSP90, due to the sustained activity of HDAC6, a PTM that protected mutp53 from degradation. We then found that mutp53 was progressively demethylated by KDM1 at lysine K370 during TG treatment, which facilitated the interaction with HSC70 involved in mutp53 protein degradation via CMA. In conclusion, this study suggests that, in colon cancer cells subjected to stress by TG, mutp53 was degraded as a consequence of demethylation at lysine K370. Therefore, specific epigenetic drugs capable of reducing constitutive methylation and/or increasing acetylation could preemptively target mutp53 and improve the outcome of endoplasmic reticulum stress-inducing treatments in tumors harboring these proteins.
Surman M, Trzos S, Wilczak M
… +2 more, Link-Lenczowski P, Przybyło M
Biochim Biophys Acta Mol Cell Res
· 2026 May · PMID 42203130
·
Publisher ↗
Transport of bioactive molecules via extracellular vesicles (EVs) is one of the mechanisms of intercellular communication. EVs regulate a number of physiological processes in recipient cells, but also contribute to devel...Transport of bioactive molecules via extracellular vesicles (EVs) is one of the mechanisms of intercellular communication. EVs regulate a number of physiological processes in recipient cells, but also contribute to development and progression of many diseases, including cancer. Many glycoproteins are incorporated into EVs, but little is known about their biological significance. Glycosylation can affect sorting of protein into EVs and interaction of EVs with the target cell. Therefore, EV glycome is being investigated for possible diagnostic and therapeutic applications. The aim of this study was structural analysis and identification of N-glycans differentiating EVs from urological cancer cell lines (bladder - T24, prostate - PC-3, and renal - Caki-2) and their non-transformed counterparts (HCV-29, HPrEC and HREpC cells, respectively) using Matrix-Assisted Laser Desorption/Ionization Time-of-Flight mass spectrometry (MALDI-TOF). EVs derived from all cancerous cell lines showed increased abundance of oligomannose structures compared to EVs from non-transformed cells. Particularly, increased expression of H8N2, H9N2 and H10N2 structures was observed in EVs derived from all 3 cancer cell lines. Also, overall sialylation was decreased in cancer-derived EVs, with lower expression of H5N4E2, H6N5E1L2 and H6N5E2L1 structures. In addition, we identified structures/subgroups of structures that distinguish EVs from each individual urological cancer cell line from EVs from reference non-transformed cells. The results provide preliminary insight into the structural diversity and biological significance of N-glycans present in EVs derived from urological cancer cells. Identifying EV N-glycan enrichment or depletion patterns that are common to, or specific for studied urological cancers may contribute to development of new diagnostic approaches.
Immune checkpoint blockade (ICB) provides limited benefit in triple-negative breast cancer (TNBC), partly due to a lactate-rich, immunosuppressive tumor microenvironment (TME). Integrative bulk and single-cell transcript...Immune checkpoint blockade (ICB) provides limited benefit in triple-negative breast cancer (TNBC), partly due to a lactate-rich, immunosuppressive tumor microenvironment (TME). Integrative bulk and single-cell transcriptomics, corroborated by tissue analyses, identify MCT4 as the predominant lactate transporter in TNBC, while supporting a context-dependent contribution of MCT1, and reveal an inverse association between MCT4 and intratumoral CD8 T cells. We therefore tested whether inhibition of monocarboxylate transporters could recondition the TME. The repurposed agent syrosingopine, a dual MCT1/MCT4 inhibitor, consistently blocked lactate export across MCT1 and MCT4 models without altering transporter/LDH abundance, and reduced tumor cell PD-L1 while restoring T-cell effector function. Syrosingopine also sensitized tumor cells to NK-cell cytotoxicity without detectable toxicity in immune cells. In immunocompetent TNBC models, syrosingopine synergized with anti-PD-1 to suppress tumor growth, remodel the immune landscape, and prolong survival, while genetic perturbation of MCTs recapitulated key metabolic and immunologic phenotypes. These findings identify tumor lactate export as an important metabolic barrier to antitumor immunity in TNBC and support MCT-targeted lactate transport inhibition as a promising strategy to reprogram the TME and improve immunotherapeutic efficacy.