Asbestos induces mesothelial cell transformation via HMGB1-driven autophagy

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.

Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma

“…In BLM-silenced macrophages, we found increased release of TNF-α, a cytokine strongly linked to asbestos-mediated carcinogenesis ( 36 , 38 – 42 ). Accordingly, Blm +/− mice injected with crocidolite had increased M1 macrophages and higher levels of TNF-α and other proinflammatory cytokines in the peritoneal lavage compared to WT.…”

“…Asbestos carcinogenesis is largely an indirect process causally linked to asbestos-induced chronic inflammation and to the release of TNF-α and of other cytokines from macrophages, which accumulate at the sites of asbestos deposition ( 36 , 38 – 42 ). We wondered whether, in vitro, by adding TNF-α, we artificially leveled any differences between WT BLM and BLM mutant cells.…”

“…3 C – G ). These cytokines, especially TNF-α and IL-1β, have been linked to asbestos carcinogenesis and play a critical role in mesothelioma development ( 36 , 38 – 42 ). No significant differences were observed in other cytokines and chemokines ( SI Appendix , Fig.…”

The Evolving Landscape of the Molecular Epidemiology of Malignant Pleural Mesothelioma

“…Indeed, experimental findings on cultures and animals showed that asbestos induces inflammation before the development of a tumor. Notably, human mesothelioma cells and macrophages upon asbestos exposure release the high mobility group box 1 (HMGB1) protein that is a key player in triggering inflammatory cascade [ 69 ] and autophagy, thus directly promoting mesothelial cells survival and malignant transformation [ 70 ]. HGBM1 acts as a nonhistone chromatin-binding protein that targets DNA and drives transcription factor assembly [ 100 ].…”

Relevance of Autophagy and Mitophagy Dynamics and Markers in Neurodegenerative Diseases

“…In pathological conditions, autophagy may have both favorable and deleterious roles. As demonstrated, a loss/gain of function in the autophagic process and increase/decrease in the expression of crucial autophagic mediators have been associated with diverse human disorders, particularly cancer [ 13 , 14 ] and neurodegeneration [ 15 ]. Most importantly, different studies have not only confirmed the importance of autophagic dynamics during neurodegeneration but also suggested that several proteins involved in this catabolic process may be considered potential markers for predicting neurodegenerative conditions [ 16 , 17 ].…”