BACKGROUND: Prostate cancer develops through malignant transformation of the prostate epithelium in a stepwise, mutation-driven process. Although activator protein-1 transcription factors such as JUN have been implicated as potential oncogenic drivers, the molecular programs contributing to prostate cancer progression are not fully understood. METHODS: We analyzed JUN expression in clinical prostate cancer samples across different stages and investigated its functional role in a Pten-deficient mouse model. We performed histopathological examinations, transcriptomic analyses and explored the senescence-associated secretory phenotype in the tumor microenvironment. RESULTS: Elevated JUN levels characterized early-stage prostate cancer and predicted improved survival in human and murine samples. Immune-phenotyping of Pten-deficient prostates revealed high accumulation of tumor-infiltrating leukocytes, particularly innate immune cells, neutrophils and macrophages as well as high levels of STAT3 activation and IL-1β production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1β and accelerated prostate tumor growth. Comparative transcriptome profiling of prostate epithelial cells revealed a senescence-associated gene signature, upregulation of pro-inflammatory processes involved in immune cell attraction and of chemokines such as IL-1β, TNF-α, CCL3 and CCL8 in Pten-deficient prostates. Strikingly, JUN depletion reversed both the senescence-associated secretory phenotype and senescence-associated immune cell infiltration but had no impact on cell cycle arrest. As a result, JUN depletion in Pten-deficient prostates interfered with the senescence-associated immune clearance and accelerated tumor growth. CONCLUSIONS: Our results suggest that JUN acts as tumor-suppressor and decelerates the progression of prostate cancer by transcriptional regulation of senescence- and inflammation-associated genes. This study opens avenues for novel treatment strategies that could impede disease progression and improve patient outcomes.

• Klíčová slova
• AP-1 transcription factors, Immune infiltration, JUN, Prostate cancer, SASP, Senescence,
• MeSH
• fosfohydroláza PTEN * genetika   metabolismus   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorové mikroprostředí * imunologie   MeSH
• nádory prostaty * patologie   genetika   metabolismus   MeSH
• progrese nemoci * MeSH
• protoonkogenní proteiny c-jun metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• sekreční fenotyp asociovaný se senescencí MeSH
• stanovení celkové genové exprese MeSH
• stárnutí buněk genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fosfohydroláza PTEN * MeSH
• protoonkogenní proteiny c-jun MeSH

The accumulation of senescent cells drives inflammaging and increases morbidity of chronic inflammatory lung diseases. Immune responses are built upon dynamic changes in cell metabolism that supply energy and substrates for cell proliferation, differentiation, and activation. Metabolic changes imposed by environmental stress and inflammation on immune cells and tissue microenvironment are thus chiefly involved in the pathophysiology of allergic and other immune-driven diseases. Altered cell metabolism is also a hallmark of cell senescence, a condition characterized by loss of proliferative activity in cells that remain metabolically active. Accelerated senescence can be triggered by acute or chronic stress and inflammatory responses. In contrast, replicative senescence occurs as part of the physiological aging process and has protective roles in cancer surveillance and wound healing. Importantly, cell senescence can also change or hamper response to diverse therapeutic treatments. Understanding the metabolic pathways of senescence in immune and structural cells is therefore critical to detect, prevent, or revert detrimental aspects of senescence-related immunopathology, by developing specific diagnostics and targeted therapies. In this paper, we review the main changes and metabolic alterations occurring in senescent immune cells (macrophages, B cells, T cells). Subsequently, we present the metabolic footprints described in translational studies in patients with chronic asthma and chronic obstructive pulmonary disease (COPD), and review the ongoing preclinical studies and clinical trials of therapeutic approaches aiming at targeting metabolic pathways to antagonize pathological senescence. Because this is a recently emerging field in allergy and clinical immunology, a better understanding of the metabolic profile of the complex landscape of cell senescence is needed. The progress achieved so far is already providing opportunities for new therapies, as well as for strategies aimed at disease prevention and supporting healthy aging.

• Klíčová slova
• cell metabolism, immune senescence, immunometabolism, inflammaging, senolytic drugs, senomorphic drugs,
• MeSH
• chronická nemoc MeSH
• chronická obstrukční plicní nemoc metabolismus   farmakoterapie   imunologie   MeSH
• lidé MeSH
• metabolické sítě a dráhy * MeSH
• plicní nemoci etiologie   farmakoterapie   metabolismus   imunologie   MeSH
• stárnutí buněk * účinky léků   MeSH
• stárnutí imunologie   metabolismus   MeSH
• zánět metabolismus   imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

ANTXR1 is one of two cell surface receptors mediating the uptake of the anthrax toxin into cells. Despite substantial research on its role in anthrax poisoning and a proposed function as a collagen receptor, ANTXR1's physiological functions remain largely undefined. Pathogenic variants in ANTXR1 lead to the rare GAPO syndrome, named for its four primary features: Growth retardation, Alopecia, Pseudoanodontia, and Optic atrophy. The disease is also associated with a complex range of other phenotypes impacting the cardiovascular, skeletal, pulmonary and nervous systems. Aberrant accumulation of extracellular matrix components and fibrosis are considered to be crucial components in the pathogenesis of GAPO syndrome, contributing to the shortened life expectancy of affected individuals. Nonetheless, the specific mechanisms connecting ANTXR1 deficiency to the clinical manifestations of GAPO syndrome are largely unexplored. In this study, we present evidence that ANTXR1 deficiency initiates a senescent phenotype in human fibroblasts, correlating with defects in nuclear architecture and actin dynamics. We provide novel insights into ANTXR1's physiological functions and propose GAPO syndrome to be reconsidered as a progeroid disorder highlighting an unexpected role for an integrin-like extracellular matrix receptor in human aging.

• MeSH
• aktiny metabolismus   MeSH
• alopecie * metabolismus   patologie   genetika   MeSH
• anodoncie * MeSH
• dědičné atrofie optického nervu genetika   metabolismus   MeSH
• fibroblasty * metabolismus   MeSH
• lidé MeSH
• mikrofilamentové proteiny * MeSH
• poruchy růstu * MeSH
• progerie genetika   patologie   metabolismus   MeSH
• receptory buněčného povrchu metabolismus   genetika   nedostatek   MeSH
• stárnutí buněk * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aktiny MeSH
• ANTXR1 protein, human MeSH Prohlížeč
• mikrofilamentové proteiny * MeSH
• receptory buněčného povrchu MeSH

CIP/KIP and INK4 families of Cyclin-dependent kinase inhibitors (CKIs) are well-established cell cycle regulatory proteins whose canonical function is binding to Cyclin-CDK complexes and altering their function. Initial experiments showed that these proteins negatively regulate cell cycle progression and thus are tumor suppressors in the context of molecular oncology. However, expanded research into the functions of these proteins showed that most of them have non-canonical functions, both cell cycle-dependent and independent, and can even act as tumor enhancers depending on their posttranslational modifications, subcellular localization, and cell state context. This review aims to provide an overview of canonical as well as non-canonical functions of CIP/KIP and INK4 families of CKIs, discuss the potential avenues to promote their tumor suppressor functions instead of tumor enhancing ones, and how they could be utilized to design improved treatment regimens for cancer patients.

• Klíčová slova
• CIP/KIP, Cancer, Cyclin-dependent kinase inhibitors, INK4, Oncogenic signaling, Posttranslational modification, Therapy,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Signal transducer and activator of transcription 3 (STAT3) signalling serves an important role in carcinogenesis and cellular senescence, and its inhibition in tumour cells represents an attractive therapeutic target. Premature cellular senescence, a process of permanent proliferative arrest of cells in response to various inducers, such as cytostatic drugs or ionizing radiation, is accompanied by morphological and secretory changes, and by altered susceptibility to chemotherapeutic agents, which can thereby complicate their eradication by cancer therapies. In the present study, the responsiveness of proliferating and docetaxel (DTX)‑induced senescent cancer cells to small molecule STAT3 inhibitor Stattic and its analogues was evaluated using tumour cell lines. These agents displayed cytotoxic effects in cell viability assays on both proliferating and senescent murine TRAMP‑C2 and TC‑1 cells; however, senescent cells were markedly more resistant. Western blot analysis revealed that Stattic and its analogues effectively inhibited constitutive STAT3 phosphorylation in both proliferating and senescent cells. Furthermore, whether the Stattic‑derived inhibitor K1836 could affect senescence induction or modulate the phenotype of senescent cells was evaluated. K1836 treatment demonstrated no effect on senescence induction by DTX. However, the K1836 compound significantly modulated secretion of certain cytokines (interleukin‑6, growth‑regulated oncogene α and monocyte chemoattractant protein‑1). In summary, the present study demonstrated differences between proliferating and senescent tumour cells in terms of their susceptibility to STAT3 inhibitors and demonstrated the ability of the new STAT3 inhibitor K1836 to affect the secretion of essential components of the senescence‑associated secretory phenotype. The present study may be useful for further development of STAT3 inhibitor‑based therapy of cancer or age‑related diseases.

• Klíčová slova
• Stattic, cellular senescence, docetaxel, senescence‑associated secretory phenotype, signal transducer and activator of transcription 3 inhibition,
• MeSH
• cytokiny * metabolismus   MeSH
• docetaxel farmakologie   MeSH
• exprese genu MeSH
• fosforylace MeSH
• myši MeSH
• stárnutí buněk MeSH
• transkripční faktor STAT3 * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cytokiny * MeSH
• docetaxel MeSH
• stattic MeSH Prohlížeč
• transkripční faktor STAT3 * MeSH

Several epidemiological studies have suggested that obesity complicated with insulin resistance and type 2 diabetes exerts deleterious effects on the skeleton. While obesity coexists with estrogen deficiency in postmenopausal women, their combined effects on the skeleton are poorly studied. Thus, we investigated the impact of high-fat diet (HFD) on bone and metabolism of ovariectomized (OVX) female mice (C57BL/6J). OVX or sham operated mice were fed either HFD (60%fat) or normal diet (10%fat) for 12 weeks. HFD-OVX group exhibited pronounced increase in body weight (~86% in HFD and ~122% in HFD-OVX, p < 0.0005) and impaired glucose tolerance. Bone microCT-scanning revealed a pronounced decrease in trabecular bone volume/total volume (BV/TV) (-15.6 ± 0.48% in HFD and -37.5 ± 0.235% in HFD-OVX, p < 0.005) and expansion of bone marrow adipose tissue (BMAT; +60.7 ± 9.9% in HFD vs. +79.5 ± 5.86% in HFD-OVX, p < 0.005). Mechanistically, HFD-OVX treatment led to upregulation of genes markers of senescence, bone resorption, adipogenesis, inflammation, downregulation of gene markers of bone formation and bone development. Similarly, HFD-OVX treatment resulted in significant changes in bone tissue levels of purine/pyrimidine and Glutamate metabolisms, known to play a regulatory role in bone metabolism. Obesity and estrogen deficiency exert combined deleterious effects on bone resulting in accelerated cellular senescence, expansion of BMAT and impaired bone formation leading to decreased bone mass. Our results suggest that obesity may increase bone fragility in postmenopausal women.

• Klíčová slova
• Aging, bone fragility, accelerated aging, bone marrow adiposity, menopause, obesity, osteoporosis, senescence,
• MeSH
• diabetes mellitus 2. typu * komplikace   MeSH
• dieta s vysokým obsahem tuků * škodlivé účinky   MeSH
• estrogeny MeSH
• kosti a kostní tkáň metabolismus   MeSH
• lidé MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• obezita komplikace   metabolismus   MeSH
• ovarektomie škodlivé účinky   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• estrogeny MeSH

Osteoporosis is defined as a systemic skeletal disease characterized by decreased bone mass and micro-architectural deterioration leading to increased fracture risk. Osteoporosis incidence increases with age in both post-menopausal women and aging men. Among other important contributing factors to bone fragility observed in osteoporosis, that also affect the elderly population, are metabolic disturbances observed in obesity and Type 2 Diabetes (T2D). These metabolic complications are associated with impaired bone homeostasis and a higher fracture risk. Expansion of the Bone Marrow Adipose Tissue (BMAT), at the expense of decreased bone formation, is thought to be one of the key pathogenic mechanisms underlying osteoporosis and bone fragility in obesity and T2D. Our review provides a summary of mechanisms behind increased Bone Marrow Adiposity (BMA) during aging and highlights the pre-clinical and clinical studies connecting obesity and T2D, to BMA and bone fragility in aging osteoporotic women and men.

• Klíčová slova
• aging, bone fragility, bone marrow adiposity, obesity, osteoporosis, type 2 diabetes (T2D),
• MeSH
• adipozita MeSH
• diabetes mellitus 2. typu * metabolismus   MeSH
• fraktury kostí * metabolismus   MeSH
• kostní dřeň patologie   MeSH
• lidé MeSH
• obezita metabolismus   MeSH
• osteoporóza * patologie   MeSH
• senioři MeSH
• stárnutí MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Replicative senescence is irreversible cell proliferation arrest for somatic cells which can be circumvented in cancers. Cellular senescence is a process, which may play two opposite roles. On the one hand, this is a natural protection of somatic cells against unlimited proliferation and malignant transformation. On the other hand, cellular secretion caused by senescence can stimulate inflammation and proliferation of adjacent cells that may promote malignancy. The main genes controlling the senescence pathways are also well known as tumor suppressors. Almost 140 genes regulate both cellular senescence and cancer pathways. About two thirds of these genes (64%) are regulated by microRNAs. Senescence-associated miRNAs can stimulate cancer progression or act as tumor suppressors. Here we review the role playing by senescence-associated miRNAs in development, diagnostics and treatment of pancreatic cancer.

• Klíčová slova
• cellular senescence, oncogene, pancreatic ductal adenocarcinoma, senescence bypass, senescence-associated miRNA, tumor suppressor,
• MeSH
• lidé MeSH
• mikro RNA * genetika   metabolismus   MeSH
• nádory slinivky břišní * genetika   patologie   MeSH
• proliferace buněk genetika   MeSH
• stárnutí buněk genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• mikro RNA * MeSH

Cellular senescence is defined as irreversible cell cycle arrest caused by various processes that render viable cells non-functional, hampering normal tissue homeostasis. It has many endogenous and exogenous inducers, and is closely connected with age, age-related pathologies, DNA damage, degenerative disorders, tumor suppression and activation, wound healing, and tissue repair. However, the literature is replete with contradictory findings concerning its triggering mechanisms, specific biomarkers, and detection protocols. This may be partly due to the wide range of cellular and in vivo animal or human models of accelerated aging that have been used to study senescence and test senolytic drugs. This review summarizes recent findings concerning senescence, presents some widely used cellular and animal senescence models, and briefly describes the best-known senolytic agents.

• Klíčová slova
• aging, cellular model, mouse model, senescence, senolytics,
• MeSH
• biologické markery MeSH
• kontrolní body buněčného cyklu MeSH
• poškození DNA MeSH
• stárnutí buněk * genetika   MeSH
• stárnutí * genetika   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• biologické markery MeSH

Cancer-associated fibroblasts (CAFs) are an essential component of the tumour microenvironment. They represent a heterogeneous group of cells that are under the control of cancer cells and can reversely influence the cancer cell population. They affect the cancer cell differentiation status, and the migration and formation of metastases. This is achieved through the production of the extracellular matrix and numerous bioactive factors. IL-6 seems to play the central role in the communication of noncancerous and cancer cells in the tumour. This review outlines the role of exosomes in cancer cells and cancer-associated fibroblasts. Available data on the exosomal cargo, which can significantly intensify interactions in the tumour, are summarised. The role of exosomes as mediators of the dialogue between cancer cells and cancer-associated fibroblasts is discussed together with their therapeutic relevance. The functional unity of the paracrine- and exosome-mediated communication of cancer cells with the tumour microenvironment represented by CAFs is worthy of attention.

• Klíčová slova
• IL-6, cancer ecosystem, cancer microenvironment, cancer-associated fibroblast, exosome,
• MeSH
• exozómy metabolismus   MeSH
• fibroblasty asociované s nádorem metabolismus   MeSH
• interleukin-6 metabolismus   MeSH
• lidé MeSH
• nádorové mikroprostředí MeSH
• nádory metabolismus   MeSH
• parakrinní signalizace MeSH
• pohyb buněk MeSH
• proliferace buněk MeSH
• regulace genové exprese u nádorů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• IL6 protein, human MeSH Prohlížeč
• interleukin-6 MeSH