ABSTRACT
Cellular senescence is a known driver of carcinogenesis and age-related diseases, yet senescence is required for various physiological processes. However, the mechanisms and factors that control the negative effects of senescence while retaining its benefits are still elusive. Here, we show that the rasGAP SH3-binding protein 1 (G3BP1) is required for the activation of the senescent-associated secretory phenotype (SASP). During senescence, G3BP1 achieves this effect by promoting the association of the cyclic GMP-AMP synthase (cGAS) with cytosolic chromatin fragments. In turn, G3BP1, through cGAS, activates the NF-κB and STAT3 pathways, promoting SASP expression and secretion. G3BP1 depletion or pharmacological inhibition impairs the cGAS-pathway preventing the expression of SASP factors without affecting cell commitment to senescence. These SASPless senescent cells impair senescence-mediated growth of cancer cells in vitro and tumor growth in vivo. Our data reveal that G3BP1 is required for SASP expression and that SASP secretion is a primary mediator of senescence-associated tumor growth.
Subject(s)
Cellular Senescence/physiology , DNA Helicases/metabolism , Neoplasms/pathology , Poly-ADP-Ribose Binding Proteins/metabolism , RNA Helicases/metabolism , RNA Recognition Motif Proteins/metabolism , A549 Cells , Animals , Carcinogenesis , Cell Line , Cell Movement , Cytokines/metabolism , DNA Helicases/antagonists & inhibitors , DNA Helicases/deficiency , Humans , Inflammation , Mice , Neoplasms/metabolism , Nucleotidyltransferases/metabolism , Poly-ADP-Ribose Binding Proteins/antagonists & inhibitors , Poly-ADP-Ribose Binding Proteins/deficiency , RNA Helicases/antagonists & inhibitors , RNA Helicases/deficiency , RNA Recognition Motif Proteins/antagonists & inhibitors , RNA Recognition Motif Proteins/deficiency , STAT3 Transcription Factor/metabolism , Signal Transduction , Transcription Factor RelA/metabolismABSTRACT
Stress granules (SGs) are membraneless organelles formed in response to insult. These granules are related to pathological granules found in age-related neurogenerative diseases such as Parkinson's and Alzheimer's. Previously, we demonstrated that senescent cells, which accumulate with age, exposed to chronic oxidative stress, are unable to form SGs. Here, we show that the senescent cells' inability to form SGs correlates with an upregulation in both the heat-shock response and autophagy pathways, both of which are well-established promoters of SG disassembly. Our data also reveals that the knockdown of HSP70 and ATG5, important components of the heat-shock response and autophagy pathways, respectively, restores the number of SGs formed in senescent cells exposed to chronic oxidative stress. Surprisingly, under these conditions, the depletion of HSP70 or ATG5 did not affect the clearance of these SGs during their recovery from chronic stress. These data reveal that senescent cells possess a unique heat-shock and autophagy-dependent ability to impair the formation of SGs in response to chronic stress, thereby expanding the existing understanding of SG dynamics in senescent cells and their potential contribution to age-related neurodegenerative diseases.
Subject(s)
Aging/physiology , Autophagy-Related Protein 5/metabolism , Autophagy/physiology , Cytoplasmic Granules/physiology , HSP70 Heat-Shock Proteins/metabolism , Heat-Shock Response/physiology , Ribonucleoproteins/metabolism , Cell Line , Cellular Senescence , Gene Expression Regulation , Humans , Oxidative Stress/physiology , Stress, PhysiologicalABSTRACT
BACKGROUND: Total joint replacement (TJR) procedures have been one of the most rewarding interventions for treating patients suffering from joint disease. However, developing a periprosthetic joint infection (PJI) is a serious complication that is associated with the highest burden of cost and reduction in patients' quality of life compared to other complications following TJRs. One of the main challenges facing clinicians who are treating PJIs is accurately diagnosing infection in a timely fashion. Multiple orthopedic associations have published clinical guidelines for diagnosing PJI which are based solely on consensus approaches, expert opinions, and narrative reviews. We believe that a higher quality of scientific rigor is necessary to establish a diagnostic guideline that represents current evidence more accurately and that identifies important knowledge gaps in PJI diagnosis. Therefore, we will conduct a systematic review on diagnostic performance of blood markers, synovial fluids, and tissue tests for diagnosing PJI. METHODS/DESIGN: Electronic search strategies will be developed and tested by an experienced medical information specialist in consultation with the review team, and gray literature will be searched using the checklist from CADTH's Grey Matters Light. Two reviewers will independently screen the literature for inclusion using the prespecified eligibility criteria. Non-English language and animal-only studies will be excluded. Quality assessment and data extractions by reviewers will be verified, and disagreements will be resolved through consensus or third party adjudication. We will assess the quality of individual studies using the QUADAS-2 tool and use GRADE to summarize the strength of body of evidence. Analyses of evidence will be conducted in accordance with the Cochrane Handbook for Diagnostic Test Accuracy Reviews. DISCUSSION: We will conduct a systemic review of tests (blood markers, synovial fluids, and tissue testing) for diagnosing PJI in patients' knee, hip, and shoulder joint replacements. This will be the first scientifically rigorous and comprehensive systematic review in the field and may feed into an evidence-based clinical practice guideline. We will compare the findings of this review with the consensus-based guides and discuss the differences, similarities, and knowledge gaps. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015023768.
