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Determination of ADP/ATP translocase isoform ratios in malignancy and cellular senescence

ABSTRACT: Cellular senescence has recently been recognized as a significant contributor to the poor prognosis of glioblastoma, one of the most aggressive brain tumors. Consequently, effectively eliminating senescent glioblastoma cells could benefit patients. Human ADP/ATP translocases (ANTs) play a role in oxidative phosphorylation in both normal and tumor cells. Previous research has shown that the sensitivity of senescent cells to mitochondria-targeted senolytics depends on the level of ANT2. In this study, we systematically mapped the transcript and protein levels of ANT isoforms in various types of senescence and glioblastoma tumorigenesis. We employed bioinformatics analysis, targeted mass spectrometry, RT-PCR, immunoblotting, and assessment of cellular energy state to elucidate how individual ANT isoforms are expressed during the development of senescence in non-cancerous and glioblastoma cells. Notably, we consistently observed an induction of ANT1 protein levels across all tested senescence types, while ANT2 and ANT3 exhibited variable changes. These alterations in ANT isoforms correlated with shifts in the cellular oxygen consumption rate. Our findings suggest that ANT isoforms are mutually interchangeable for oxidative phosphorylation, and manipulating individual ANT isoforms could be a potential target for senolytic therapy.

ORGANISM(S): Homo Sapiens

SUBMITTER: Marie Vajrychova

PROVIDER: PXD029523 | panorama | Mon Apr 28 00:00:00 BST 2025

REPOSITORIES: PanoramaPublic

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Project description:In response to environmental stressors and a variety of inflammatory cytokines, p38 MAPKs become directly activated. Here we report the human glucocorticoid receptor (GR) Serine 134 as a novel target for p38 MAPK. Unlike most other phosphorylation events that occur on the GR, phosphorylation of Ser134 was found to be hormone-independent in several human and rat cell types. Instead we found phosphorylation of Ser134 was induced by a variety of stress-activating stimuli, including: glucose starvation, ultraviolet irradiation, osmotic shock, and oxidative stress. Pharmacological inhibitors and shRNA-mediated knockdown experiments correlate this phosphorylation with the activation of p38 MAPK. Compared to wild-type GR, cells expressing a mutant receptor incapable of phosphorylation at Ser134 (S134A GR) had a significantly altered hormone-dependent genome-wide transcriptional response to glucocorticoids. Moreover, we show that although WT GR regulated roughly half as many genes as S134A GR, WT receptor selectively activated significantly more genes associated with endocrine and inflammatory disease than the mutant receptor, suggesting that the phosphorylation status of Ser134 is critical for modulating GR function. Phosphorylation of Ser134 did not alter either nuclear translocation or the stability of the GR protein in the absence or presence of ligand. However, phosphorylation of Ser134 significantly increased the association of the GR with the zeta isoform the 14-3-3 class of signaling proteins, resulting in a blunted hormone-dependent transcriptional response of LAD1 and IGFBP1 but not GILZ. Together these data suggest that the phosphorylation of Ser134 acts as a molecular sensor on the GR, monitoring the level of cellular stress to allow for altered 14-3-3zeta cofactor association, ultimately modifying glucocorticoid signaling in a gene-dependent manner. Our results reveal one mechanism that may allow cellular stress to dictate the transcriptional response of cells to hormone. U2OS cells, a human osteosarcoma cell line, were transfected with either WT GR or S134A GR and put under antibiotic selection to produce a stable mixed population of cells expressing comparable levels of GR. 10^6 cells were treated with 100nM Dexamethasone (DEX) or vehicle control for 6 hours. Three biological and one hybridization replicate are included for each sample.

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Determination of ADP/ATP translocase isoform ratios in malignancy and cellular senescence

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