bims-stacyt 2025-10-19 papers

Biochim Biophys Acta Mol Basis Dis. 2025 Oct 14. pii: S0925-4439(25)00420-X. [Epub ahead of print] 168072

Multiverse of phosphorglycerate kinase: Exploring canonical, moonlighting, and tumor microenvironmental functions.

Han-Hsi Kuo, Zhao-Jing He, Phi Ngoc Tram, Hee-Do Kim, Cheorl-Ho Kim, Yu-Chan Chang.

The phosphoglycerate kinase family includes PGK1 and PGK2, which are traditionally characterized as typical glycolytic enzymes responsible for catalyzing the generation of ATP during glucose metabolism. However, accumulating evidence has uncovered a broad array of non-canonical, non-enzymatic "moonlighting" functions associated with these proteins. Beyond their metabolic roles, PGK1 and PGK2 are increasingly recognized as multifunctional regulators in cancer biology-modulating intracellular signaling pathways, remodeling the extracellular matrix, shaping immune responses, and promoting metastasis. Notably, their functions are context-dependent and spatially organized within the tumor microenvironment (TME), where they may act as adaptive stress sensors and immune response sculptors. While previous studies have primarily focused on transcriptional regulation and enzymatic kinetics, this review provides a thorough reevaluation of PGK's moonlighting functions in tumor progression and the TME. We highlight emerging evidence supporting their involvement in extracellular signaling, stress adaptation, and immune evasion, while also integrating various novel post-translational modifications of PGKs. This perspective may offer novel therapeutic avenues by targeting their non-enzymatic, cancer-promoting activities.

Keywords: Immune response; Moonlighting; Phosphoglycerate kinase; Post-translational modification; Tumor microenvironment

DOI: https://doi.org/10.1016/j.bbadis.2025.168072

J Biol Chem. 2025 Oct 14. pii: S0021-9258(25)02670-5. [Epub ahead of print] 110818

Loss of O-GlcNAcylation in cardiac myocytes triggers the integrated stress response contributing to heart failure.

Kyriakos N Papanicolaou, Wenxi Zhang, Aidan Dunphy, Justin C Zhong, Clara Y Cho, Dan R Turner, Deepthi Ashok, D Brian Foster, Brian O'Rourke, Natasha E Zachara.

Heart failure (HF) is a significant global health problem, affecting an estimated 64 million people worldwide. At the core of HF is the progressive dysfunction and irreversible loss of cardiac myocytes. O-GlcNAc transferase (OGT) is a conserved enzyme that catalyzes the addition of N-acetyl glucosamine (GlcNAc) to serine or threonine residues of intracellular proteins. This dynamic protein modification, termed O-GlcNAcylation, has been implicated in nutrient sensing, metabolic regulation and stress adaptation. The integrated stress response (ISR) is a pathway that enables cells to rapidly respond to acute environmental changes and cell damage. During ISR, the translation factor eIF2α is phosphorylated shutting down general translation but favoring the rapid production of stress-adaptive proteins. However, prolonged activation of the ISR can be detrimental to cells. In this study, we found that inhibiting OGT activates the GCN2/eIF2α/Atf4 signaling axis of the ISR. Activation of this pathway could be blocked by ISRIB, a small molecule that opposes the activity of phosphorylated eIF2α. Mice with inducible deletion of OGT in adult cardiomyocytes developed HF, and treatment with ISRIB significantly delayed the progression to HF. Our study reveals the regulatory impact of O-GlcNAcylation on the ISR and highlights a new potential strategy for alleviating HF.

Keywords: Atf4; GCN2; ISRIB; OGT; PERK; cardiomyocytes; cardiomyopathy; eIF2α; mTOR; translation initiation

DOI: https://doi.org/10.1016/j.jbc.2025.110818

Int J Mol Sci. 2025 Oct 03. pii: 9666. [Epub ahead of print]26(19):

When Fat Talks: How Adipose-Derived Extracellular Vesicles Fuel Breast Cancer.

Maria Pia Cavaleri, Tommaso Pusceddu, Lucia Sileo, Luna Ardondi, Ilaria Vitali, Ilenia Pia Cappucci, Laura Basile, Giuseppe Pezzotti, Francesco Fiorica, Letizia Ferroni, Barbara Zavan.

Adipose tissue plays a crucial role in the tumor microenvironment (TME), where its secreted extracellular vesicles (EVs) are involved in the complex signaling between tumor cells and surrounding stromal components. This study aims to unravel the mechanisms through which adipocyte-derived EVs influence breast cancer (BC) progression. Human mesenchymal stem cells (hMSCs) were differentiated into adipocytes following a 21-day induction protocol that led to significant accumulation of lipid droplets within the cells. EVs were isolated from the conditioned medium of both hMSC-derived adipocytes and BC cells. Particle size distribution, morphology, and uptake into the recipient cell were investigated via nanoparticle tracking analysis, transmission electron microscopy, and fluorescence microscopy, respectively. Our results show that BC-derived EVs notably impaired cell viability and modulated the expression of key genes involved in apoptosis resistance within stromal cells. On the other hand, stromal-derived EVs significantly altered tumor cell behavior, indicating a dynamic, bidirectional exchange of bioactive signals. These findings underscore the pivotal role of EV-mediated communication in the tumor-stroma interplay, suggesting that adipocyte-cancer cell EV crosstalk contributes to the remodeling of the TME, potentially facilitating tumor progression.

Keywords: adipocyte; breast cancer cells; exosome; extracellular vesicles

DOI: https://doi.org/10.3390/ijms26199666

Front Immunol. 2025 ;16 1674163

Endoplasmic reticulum stress orchestrates tumor metabolism and immunity: new insights into immunometabolic therapeutics.

Zhang Fu, Mengyue Li, Huaixiang Zhou, Xin Zhong, Zhiqiang Zhang, Xianwen Meng, Youheng Jiang, Tao Wang, Ningning Li.

Endoplasmic reticulum (ER) stress and its adaptive signaling network have emerged as central regulators of tumor progression, metabolic rewiring, and immune modulation. Within the nutrient-deprived and hypoxic tumor microenvironment, ER stress reprograms glucose, lipid, and amino acid metabolism, exerting context-dependent effects that influence both tumor cell viability and immune regulation. Concurrently, ER stress remodels the metabolic fitness and functional states of immune cells, influencing T cell exhaustion, macrophage polarization, and dendritic cell maturation. Emerging evidence indicates that tumor- and immune-cell-derived metabolites (e.g., lactate, fatty acids, and tryptophan derivatives) exert both metabolic and immunomodulatory functions, thereby shaping a dynamic "ER stress-metabolism-immunity" axis that underlies cancer heterogeneity, immune evasion, and therapeutic resistance. In this review, we synthesize recent advances delineating how canonical ER stress pathways intersect with immunometabolic reprogramming across tumor and immune compartments, and we discuss how this integrated axis reshapes the tumor immune microenvironment (TIME). Targeting this integrated axis may unveil new strategies to overcome metabolic vulnerabilities and enhance the efficacy of immunotherapy.

Keywords: endoplasmic reticulum stress; immunometabolism; metabolic reprogramming; tumor immune microenvironment; unfolded protein response

DOI: https://doi.org/10.3389/fimmu.2025.1674163

Biosci Biotechnol Biochem. 2025 Oct 13. pii: zbaf147. [Epub ahead of print]

Activating transcription factor 4 mediates rare sugar-induced transactivation of the fibroblast growth factor 21 promoter.

Oulan G H N B Efendi, Sho Matsui, Mai Tsukamoto, Yasuo Oguri, Satoshi Tsuzuki, Tsutomu Sasaki.

Sugar intake induces the secretion of fibroblast growth factor 21 (FGF21) from the liver. Subsequently, FGF21 acts on the hypothalamus to reduce sugar intake. As simple sugars are obesogenic, low-calorie rare sugars can be used as alternatives. Accordingly, D-allulose, D-tagatose, and D-sorbitol induce Fgf21 expression in primary mouse hepatocytes. Carbohydrate-responsive element-binding protein regulates simple sugar-induced FGF21 expression. Therefore, this study aimed to determine whether the same mechanism was responsible for rare sugar-induced FGF21 expression. Promoter analysis, knockdown assays, and chromatin immunoprecipitation were performed using primary mouse hepatocytes. Our findings demonstrate that these three rare sugars transactivate mouse Fgf21 promoter by inducing activating transcription factor 4 (ATF4), which binds to an amino acid response element located 1,027 base pairs upstream of the transcription start site. These results suggested a novel mechanism for sugar-induced FGF21 expression.

Keywords: activating transcription factor 4; amino acid response element; fibroblast growth factor 21; rare sugars

DOI: https://doi.org/10.1093/bbb/zbaf147

Cell Commun Signal. 2025 Oct 17. 23(1): 443

Crosstalk between tumor endothelial cells and cancer cells is important for metastasis initiation.

Victor Oginga Oria, Joana Leitao Castro, Jéssica de Pina Roque, Alejandro Gutierrez Martinez, Freia Isak Jørgensen, Marie Vestergaard Lukassen, Leonor Rib, Mia Kristine Grønning Høg, Kasper Johansen Mygind, Janine Terra Erler.

BACKGROUND: Metastasis is a major contributor of cancer-related mortality and involves complex crosstalk between cancer cells and stromal cells modulated by various cytokines and growth factors. While the endothelium is essential for supplying nutrients and oxygen, little is known about its role in metastasis initiation. Determining the effect of endothelial-derived angiocrine factors on cancer cells may explain the mechanisms regulating metastasis initiation.
RESULTS: In this study, we investigated the role of normal endothelial cells (NEC) and tumor endothelial cells (TEC) in regulating the rate-limiting steps of metastasis initiation. First, we demonstrated that TEC have a higher proliferation, migration, and angiogenic potential than NEC. TEC-conditioned media significantly promoted chemotaxis, invasion, and proliferation of cancer cells relative to NEC-conditioned media. Additionally, TEC facilitated faster cell-cell adhesion to tumor cells than NEC. Mass spectrometry analysis of endothelial cell secretome revealed higher levels of PDGF-AA, PDGF-C, and VEGFA in TEC-conditioned medium, which were associated with enriched PI3K-AKT, MAPK, and RAS signaling pathways, as well as regulation of actin cytoskeleton and focal adhesion. In vitro functional studies using recombinant proteins showed that PDGF-AA and PDGF-C significantly promoted cancer cell chemotaxis and invasion without affecting proliferation. However, unlike VEGFA, PDGF-AA and PDGF-C did not affect endothelial cell tube formation or vascular permeability. Interestingly, neutralization of TEC-derived PDGF-C signficantly inhibited tumor cell chemotaxis and invasion, and attenuated EphA2/AKT/P38/ERK signaling in vitro. In vivo, the co-injection of TEC and 4T1 cells resulted in significantly higher primary breast tumor growth and liver metastasis in an orthotopic mouse model.
CONCLUSION: Our results demonstrate that crosstalk between cancer cells and TEC, partly through angiocrine factors in the TME, induces the rate-limiting steps of metastasis initiation.

Keywords: Angiocrine factors; Endothelium; Metastasis; NEC; TEC

DOI: https://doi.org/10.1186/s12964-025-02441-3