Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression.

Abstract

High-mobility group box 1 (HMGB1) is an inflammatory molecule that has a critical role in the initiation and progression of malignant mesothelioma (MM). Aspirin (acetylsalicylic acid, ASA) is the most widely used nonsteroidal anti-inflammatory drug that reduces the incidence, metastatic potential and mortality of many inflammation-induced cancers. We hypothesized that ASA may exert anticancer properties in MM by abrogating the carcinogenic effects of HMGB1. Using HMGB1-secreting and -non-secreting human MM cell lines, we determined whether aspirin inhibited the hallmarks of HMGB1-induced MM cell growth in vitro and in vivo. Our data demonstrated that ASA and its metabolite, salicylic acid (SA), inhibit motility, migration, invasion and anchorage-independent colony formation of MM cells via a novel HMGB1-mediated mechanism. ASA/SA, at serum concentrations comparable to those achieved in humans taking therapeutic doses of aspirin, and BoxA, a specific inhibitor of HMGB1, markedly reduced MM growth in xenograft mice and significantly improved survival of treated animals. The effects of ASA and BoxA were cyclooxygenase-2 independent and were not additive, consistent with both acting via inhibition of HMGB1 activity. Our findings provide a rationale for the well documented, yet poorly understood antitumorigenic activity of aspirin, which we show proceeds via HMGB1 inhibition. Moreover, the use of BoxA appears to allow a more efficient HMGB1 targeting while eluding the known gastrointestinal side effects of ASA. Our findings are directly relevant to MM. Given the emerging importance of HMGB1 and its tumor-promoting functions in many cancer types, and of aspirin in cancer prevention and therapy, our investigation is poised to provide broadly applicable information.

• Authors: H Yang, L Pellegrini, A Napolitano, C Giorgi, S Jube, A Preti, C J Jennings, F De Marchis, E G Flores, D Larson, I Pagano, M Tanji, A Powers, S Kanodia, G Gaudino, S Pastorino, H I Pass, P Pinton, M E Bianchi, M Carbone
• Journal: Cell death & disease (Cell Death Dis) Vol. 6 Pg. e1786 (Jun 11 2015) ISSN: 2041-4889 [Electronic] England
• PMID: 26068794 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antineoplastic Agents
• HMGB1 Protein
• HMGB1 protein, mouse
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Salicylic Acid
• Aspirin

Topics

• 3T3 Cells
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (therapeutic use)
• Antineoplastic Agents (therapeutic use)
• Aspirin (therapeutic use)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cyclooxygenase 2 (genetics, metabolism)
• Epithelial-Mesenchymal Transition (drug effects)
• Female
• HMGB1 Protein (antagonists & inhibitors, metabolism)
• Lung Neoplasms (drug therapy, metabolism)
• Mesothelioma (drug therapy, metabolism)
• Mesothelioma, Malignant
• Mice
• Mice, Knockout
• Mice, SCID
• Neoplasm Invasiveness (pathology)
• Salicylic Acid (therapeutic use)
• Xenograft Model Antitumor Assays