Induction of senescence by chemotherapeutic agents arrests cancer cells and activates immune surveillance responses to contribute to therapy outcomes. In this investigation, we searched for ways to enhance the NK-mediated elimination of senescent cells. We used a staggered screen approach, first identifying siRNAs potentiating the secretion of immunomodulatory cytokines to later test for their ability to enhance NK-mediated killing of senescent cells. We identified that genetic or pharmacological inhibition of SMARCA4 enhanced senescent cell elimination by NK cells. SMARCA4 expression is elevated during senescence and its inhibition derepresses repetitive elements, inducing the SASP via activation of cGAS/STING and MAVS/MDA5 pathways. Moreover, a PROTAC targeting SMARCA4 synergized with cisplatin to increase the infiltration of CD8 T cells and mature, activated NK cells in an immunocompetent model of ovarian cancer. Our results indicate that SMARCA4 inhibitors enhance NK-mediated surveillance of senescent cells and may represent senotherapeutic interventions for ovarian cancer.

• MeSH
• buňky NK * imunologie   metabolismus   MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• cisplatina farmakologie   MeSH
• DNA-helikasy * genetika   metabolismus   antagonisté a inhibitory   MeSH
• jaderné proteiny * genetika   metabolismus   antagonisté a inhibitory   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory vaječníků imunologie   patologie   genetika   metabolismus   farmakoterapie   MeSH
• nukleotidyltransferasy metabolismus   MeSH
• signální transdukce MeSH
• stárnutí buněk * imunologie   genetika   účinky léků   MeSH
• transkripční faktory * genetika   metabolismus   antagonisté a inhibitory   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cisplatina MeSH
• DNA-helikasy * MeSH
• jaderné proteiny * MeSH
• nukleotidyltransferasy MeSH
• SMARCA4 protein, human MeSH Prohlížeč
• transkripční faktory * 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

Anchoring of heterochromatin to the nuclear envelope appears to be an important process ensuring the spatial organization of the chromatin structure and genome function in eukaryotic nuclei. Proteins of the inner nuclear membrane (INM) mediating these interactions are able to recognize lamina-associated heterochromatin domains (termed LAD) and simultaneously bind either lamin A/C or lamin B1. One of these proteins is the lamin B receptor (LBR) that binds lamin B1 and tethers heterochromatin to the INM in embryonic and undifferentiated cells. It is replaced by lamin A/C with specific lamin A/C binding proteins at the beginning of cell differentiation and in differentiated cells. Our functional experiments in cancer cell lines show that heterochromatin in cancer cells is tethered to the INM by LBR, which is downregulated together with lamin B1 at the onset of cell transition to senescence. The downregulation of these proteins in senescent cells leads to the detachment of centromeric repetitive sequences from INM, their relocation to the nucleoplasm, and distension. In cells, the expression of LBR and LB1 is highly coordinated as evidenced by the reduction of both proteins in LBR shRNA lines. The loss of the constitutive heterochromatin structure containing LADs results in changes in chromatin architecture and genome function and can be the reason for the permanent loss of cell proliferation in senescence.

• Klíčová slova
• cellular senescence, centromere-specific satellite heterochromatin, constitutive heterochromatin, heterochromatin tether, lamin A/C, lamin B receptor, lamin B1,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH