Back to Search
Start Over
Cancer-derived exosomal TRIM59 regulates macrophage NLRP3 inflammasome activation to promote lung cancer progression.
- Source :
-
Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2020 Aug 31; Vol. 39 (1), pp. 176. Date of Electronic Publication: 2020 Aug 31. - Publication Year :
- 2020
-
Abstract
- Background: Exosomes are emerging as important mediators of the cross-talk between tumor cells and the microenvironment. The communication between tumor-derived exosomes and macrophages has a critical role in facilitating tumor progression. However, the mechanisms by which exosomes modulate tumor development in lung cancer are not fully understood.<br />Methods: Short hairpin RNA mediated knockdown or exogenous expression of TRIM59 combined with in vitro and in vivo assays were performed to prove the functional significance of TRIM59. Western blotting, real-time PCR, co-immunoprecipitation, immunofluorescence (IF) staining assays, proximity ligation assay (PLA), ubiquitination assays, lactate secretion and lipid droplets content measurement, and rescue experiments were used to evaluate the mechanism. Lewis lung carcinoma (LLC) cells were injected via subcutaneously or tail vein into C57BL/6 wild-type (WT) and transgenic mice to assess the role of TRIM59 in vivo.<br />Results: We demonstrated that tripartite motif-containing 59 (TRIM59) was expressed in lung cancer cells-derived exosomes, and can be transferred to macrophages through the exosomes. Activated macrophages by TRIM59 promote lung cancer progression in vitro and in vivo. Mechanistic investigations revealed that TRIM59 physically interacts with abhydrolase domain containing 5 (ABHD5) and directly induced the ubiquitination of ABHD5 and led to its proteasome-dependent degradation. ABHD5, an lipolytic co-activator, deficiency induced metabolic reprogramming and enabled NLRP3 inflammasome activation in macrophages. Further studies showed that the exacerbation of NLRP3 inflammasome activation by ABHD5 deficiency, provides a positive feedback loop to promote cancer progression by preferentially secrete the proinflammatory cytokine IL-1β.<br />Conclusions: Collectively, these data indicate that tumor-derived exosomal TRIM59 converts macrophages to tumor-promoting functions of macrophages via regulating ABHD5 proteasomal degradation, to activate NLRP3 inflammasome signaling pathway to promote lung cancer progression by IL-1β secretion. Our findings also indicate that tumor-derived exosomal TRIM59 has an important role in intercellular communication for fostering an inflammatory microenvironment and promoting lung metastasis.
- Subjects :
- Animals
Apoptosis
Biomarkers, Tumor genetics
Biomarkers, Tumor metabolism
Carcinoma, Lewis Lung immunology
Carcinoma, Lewis Lung metabolism
Cell Proliferation
Humans
Inflammasomes metabolism
Intracellular Signaling Peptides and Proteins genetics
Lung Neoplasms immunology
Lung Neoplasms metabolism
Macrophages immunology
Macrophages metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
NLR Family, Pyrin Domain-Containing 3 Protein genetics
Tripartite Motif Proteins genetics
Tumor Cells, Cultured
Tumor Microenvironment
Carcinoma, Lewis Lung pathology
Exosomes metabolism
Gene Expression Regulation, Neoplastic
Intracellular Signaling Peptides and Proteins metabolism
Lung Neoplasms secondary
Macrophages pathology
NLR Family, Pyrin Domain-Containing 3 Protein metabolism
Tripartite Motif Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1756-9966
- Volume :
- 39
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of experimental & clinical cancer research : CR
- Publication Type :
- Academic Journal
- Accession number :
- 32867817
- Full Text :
- https://doi.org/10.1186/s13046-020-01688-7