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Radiation-induced abscopal reproductive effect is driven by TNF-α/p38 MAPK/Rac1 axis in Sertoli cells.

ABSTRACT: Rationale: Radiotherapy has become a mainstay for tumor management, and more than 50% of patients with thoracic tumor need to be treated with radiotherapy. However, the potential adverse effects of thoracic radiotherapy on the reproductive system remain elusive. Methods: Western blot analysis, immunofluorescence assay and transmission electron microscopy (TEM) analysis were performed to investigate the integrity of blood-testis barrier (BTB) in male mice after hypofractionated irradiation (IR) on the right thorax. RNA sequencing, co-immunoprecipitation (IP), Duolink PLA and inhibitor experiments were carried out to demonstrate the molecular mechanisms of the BTB dynamics changes and the subsequent reproductive effect. Results: It was found that the hypofractionated IR on right thorax evoked ultrastructural destruction in distant testes, and thus caused radiation-induced abscopal reproductive effect (RIARE) in male mice. Mechanistically, thoracic IR induced significant nuclear translocation of Rac Family Small GTPase 1 (Rac1) in abscopal Sertoli cells, which closely correlated with the activation of TNF-α/p38 mitogen activated protein kinase (MAPK) pathway. Of note, YWHAZ, a critical polarity protein, was found to be co-localized with Rac1 in Sertoli cells, and this interaction was indispensable for thoracic IR-induced Rac1 nuclear translocation and subsequent degradation of BTB-associated proteins. Conclusions: Our findings imply for the first time that YWHAZ-mediated Rac1 nuclear translocation plays central roles in RIARE, and TNF-α/p38 MAPK/Rac1 axis can be employed as a therapeutic target against RIARE for young male patients receiving hypofractionated radiotherapy.

SUBMITTER: Hu S

PROVIDER: S-EPMC8058717 | biostudies-literature |

REPOSITORIES: biostudies-literature

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circBTBD7 Promotes Immature Porcine Sertoli Cell Growth through Modulating miR-24-3p/MAPK7 Axis to Inactivate p38 MAPK Signaling Pathway.

Project description:Sertoli cells are the crucial coordinators to guarantee normal spermatogenesis and male fertility. Although circular RNAs (circRNAs) exhibit developmental-stage-specific expression in porcine testicular tissues and have been thought of as potential regulatory molecules in spermatogenesis, their functions and mechanisms of action remain largely unknown, especially in domestic animals. A novel circBTBD7 was identified from immature porcine Sertoli cells using reverse transcription PCR, Sanger sequencing, and fluorescence in situ hybridization assays. Functional assays illustrated that circBTBD7 overexpression promoted cell cycle progression and cell proliferation, as well as inhibited cell apoptosis in immature porcine Sertoli cells. Mechanistically, circBTBD7 acted as a sponge for the miR-24-3p and further facilitated its target mitogen-activated protein kinase 7 (MAPK7) gene. Overexpression of miR-24-3p impeded cell proliferation and induced cell apoptosis, which further attenuated the effects of circBTBD7 overexpression. siRNA-induced MAPK7 deficiency resulted in a similar effect to miR-24-3p overexpression, and further offset the effects of miR-24-3p inhibition. Both miR-24-3p overexpression and MAPK7 knockdown upregulated the p38 phosphorylation activity. The SB202190 induced the inhibition of p38 MAPK pathway and caused an opposite effect to that of miR-24-3p overexpression and MAPK7 knockdown. Collectively, circBTBD7 promotes immature porcine Sertoli cell growth through modulating the miR-24-3p/MAPK7 axis to inactivate the p38 MAPK signaling pathway. This study expanded our knowledge of noncoding RNAs in porcine normal spermatogenesis through deciding the fate of Sertoli cells.

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Rac1/Pak1/p38/MMP-2 Axis Regulates Angiogenesis in Ovarian Cancer.

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Involvement of p38-βTrCP-Tristetraprolin-TNFα axis in radiation pneumonitis.

Project description:Early release of tumor necrosis factor-alpha (TNF-α) during radiotherapy of thoracic cancers plays an important role in radiation pneumonitis, whose inhibition may provide lung radioprotection. We previously reported radiation inactivates Tristetraprolin (TTP), a negative regulator of TNF-α synthesis, which correlated with increased TNF-α release. However, the molecular events involved in radiation-induced TTP inactivation remain unclear. To determine if eliminating Ttp in mice resulted in a phenotypic response to radiation, Ttp-null mice lungs were exposed to a single dose of 15 Gy, and TNF-α release and lung inflammation were analyzed at different time points post-irradiation. Ttp-/- mice with elevated (9.5±0.6 fold) basal TNF-α showed further increase (12.2±0.9 fold, p<0.02) in TNF-α release and acute lung inflammation within a week post-irradiation. Further studies using mouse lung macrophage (MH-S), human lung fibroblast (MRC-5), and exogenous human TTP overexpressing U2OS and HEK293 cells upon irradiation (a single dose of 4 Gy) promoted p38-mediated TTP phosphorylation at the serine 186 position, which primed it to be recognized by an ubiquitin ligase (E3), beta transducing repeat containing protein (β-TrCP), to promote polyubiquitination-mediated proteasomal degradation. Consequently, a serine 186 to alanine (SA) mutant of TTP was resistant to radiation-induced degradation. Similarly, either a p38 kinase inhibitor (SB203580), or siRNA-mediated β-TrCP knockdown, or overexpression of dominant negative Cullin1 mutants protected TTP from radiation-induced degradation. Consequently, SB203580 pretreatment blocked radiation-induced TNF-α release and radioprotected macrophages. Together, these data establish the involvement of the p38-βTrCP-TTP-TNFα signaling axis in radiation-induced lung inflammation and identified p38 inhibition as a possible lung radioprotection strategy.

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The p38 MAPK-MK2 axis regulates E2F1 and FOXM1 expression after epirubicin treatment.

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| S-EPMC3447739 | biostudies-literature

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Project description:p38 mitogen-activated protein kinases (MAPKs) respond to a wide range of extracellular stimuli. While the inhibition of p38 signaling is implicated in the impaired capacity to repair ultraviolet (UV)-induced DNA damage-a primary risk factor for human skin cancers-its mechanism of action in skin carcinogenesis remains unclear, as both anti-proliferative and survival functions have been previously described. In this study, we utilized cultured keratinocytes, murine tumorigenesis models, and human cutaneous squamous cell carcinoma (SCC) specimens to assess the effect of p38 in this regard. UV irradiation of normal human keratinocytes increased the expression of all four p38 isoforms (?/?/?/?); whereas irradiation of p53-deficient A431 keratinocytes derived from a human SCC selectively decreased p38?, without affecting other isoforms. p38? levels are decreased in the majority of human cutaneous SCCs assessed by tissue microarray, suggesting a tumor-suppressive effect of p38? in SCC pathogenesis. Genetic and pharmacological inhibition of p38? and in A431 cells increased cell proliferation, which was in turn associated with increases in NAPDH oxidase (NOX2) activity as well as intracellular reactive oxygen species (ROS). These changes led to enhanced invasiveness of A431 cells as assessed by the matrigel invasion assay. Chronic treatment of p53-/-/SKH-1 mice with the p38 inhibitor SB203580 accelerated UV-induced SCC carcinogenesis and increased the expression of NOX2. NOX2 knockdown suppressed the augmented growth of A431 xenografts treated with SB203580. These findings indicate that in the absence of p53, p38? deficiency drives SCC growth and progression that is associated with enhanced NOX2 expression and ROS formation.

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A BMP4-p38 MAPK signaling axis controls ISL1 protein stability and activity during cardiogenesis.

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| S-EPMC8365108 | biostudies-literature

Macrophage contributes to radiation-induced anti-tumor abscopal effect on transplanted breast cancer by HMGB1/TNF-α signaling factors.

Project description:Objectives: The roles of innate immunity including macrophages in radiation-induced abscopal effect (RIAE) are ambiguous. In this study, we evaluated the role of macrophage in RIAE and the interaction of cytokines in tumor microenvironment after irradiation. Materials and Methods: Transplanted tumor of breast cancer cells in BalB/C mice, severe combined immunodeficiency (SCID) mice and non-obese diabetic (NOD)-SCID mice were irradiated with fractionation doses to observe anti-tumor abscopal effect. The underlying mechanism of RIAE was investigated by treating the mice with TNF-α inhibitor or macrophage depletion drug and analyzing the alteration of macrophage distribution in tumors. A co-culture system of breast cancer cells and macrophages was applied to disclose the signaling factors and related pathways involved in the RIAE. Results: The growth of nonirradiated tumor was effectively suppressed in mice with normal or infused macrophages but not in mice with insufficiency/depletion of macrophage or TNF-α inhibition, where M1-macrophage was mainly involved. Investigation of the bystander signaling factors in vitro demonstrated that HMGB1 released from irradiated breast cancer cells promoted bystander macrophages to secret TNF-α through TLR-4 pathway and further inhibited the proliferation and migration of non-irradiated cancer cells by PI3K-p110γ suppression. Conclusions: HMGB1 and TNF-α contributes to M1-macrophages facilitated systemic anti-tumor abscopal response triggered by radiotherapy in breast cancer, indicating that the combination of immunotherapy and radiotherapy may has important implication in enhancing the efficiency of tumor treatment.

| S-EPMC8040298 | biostudies-literature

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Project description:Nutrients are absorbed solely by the intestinal villi. Aging of this organ causes malabsorption and associated illnesses, yet its aging mechanisms remain unclear. Here, we show that aging-caused intestinal villus structural and functional decline is regulated by mTORC1, a sensor of nutrients and growth factors, which is highly activated in intestinal stem and progenitor cells in geriatric mice. These aging phenotypes are recapitulated in intestinal stem cell-specific Tsc1 knockout mice. Mechanistically, mTORC1 activation increases protein synthesis of MKK6 and augments activation of the p38 MAPK-p53 pathway, leading to decreases in the number and activity of intestinal stem cells as well as villus size and density. Targeting p38 MAPK or p53 prevents or rescues ISC and villus aging and nutrient absorption defects. These findings reveal that mTORC1 drives aging by augmenting a prominent stress response pathway in gut stem cells and identify p38 MAPK as an anti-aging target downstream of mTORC1.

| S-EPMC6940394 | biostudies-literature

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