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Asbestos induces mesothelial cell transformation via HMGB1-driven autophagy.
- Source :
- Proceedings of the National Academy of Sciences of the United States of America; 10/13/2020, Vol. 117 Issue 41, p1-10, 10p
- Publication Year :
- 2020
-
Abstract
- Asbestos causes malignant transformation of primary human mesothelial cells (HM), leading to mesothelioma. The mechanisms of asbestos carcinogenesis remain enigmatic, as exposure to asbestos induces HM death. However, some asbestos-exposed HM escape cell death, accumulate DNA damage, and may become transformed. We previously demonstrated that, upon asbestos exposure, HM and reactive macrophages releases the high mobility group box 1 (HMGB1) protein that becomes detectable in the tissues near asbestos deposits where HMGB1 triggers chronic inflammation. HMGB1 is also detectable in the sera of asbestos-exposed individuals and mice. Searching for additional biomarkers, we found higher levels of the autophagy marker ATG5 in sera from asbestos-exposed individuals compared to unexposed controls. As we investigated the mechanisms underlying this finding, we discovered that the release of HMGB1 upon asbestos exposure promoted autophagy, allowing a higher fraction of HM to survive asbestos exposure. HMGB1 silencing inhibited autophagy and increased asbestos-induced HM death, thereby decreasing asbestos-induced HM transformation. We demonstrate that autophagy was induced by the cytoplasmic and extracellular fractions of HMGB1 via the engagement of the RAGE receptor and Beclin 1 pathway, while nuclear HMGB1 did not participate in this process. We validated our findings in a novel unique mesothelial conditional HMGB1-knockout (HMGB1-cKO) mouse model. Compared to HMGB1 wild-type mice, mesothelial cells from HMGB1-cKO mice showed significantly reduced autophagy and increased cell death. Autophagy inhibitors chloroquine and desmethylclomipramine increased cell death and reduced asbestos-driven foci formation. In summary, HMGB1 released upon asbestos exposure induces autophagy, promoting HM survival and malignant transformation. [ABSTRACT FROM AUTHOR]
- Subjects :
- CELL transformation
ASBESTOS
CELL death
DNA damage
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 117
- Issue :
- 41
- Database :
- Complementary Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 146453127
- Full Text :
- https://doi.org/10.1073/pnas.2007622117