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.
Highlights
MM and a similar number dies of this almost invariably fatal disease.[1]
We report that salicylates inhibit the activities of extracellular high-mobility group box 1 (HMGB1) and that at least part of the anticancer effects of aspirin are due to inhibition of HMGB1’s activities and are cyclooxygenase enzymes (COX)-2 independent
Studies have shown that: (i) other nonsteroidal anti-inflammatory drug (NSAID) that, similar to aspirin, inhibit COX activity, reduce cancer risk, (ii) COX-2 is overexpressed in many tumors, and (iii) Ptgs[2] (Cox-2)-null mice have much reduced number of precancerous colon polyps.[27]
Summary
MM and a similar number dies of this almost invariably fatal disease.[1]. Major risk factors for MM are exposure to asbestos and erionite mineral fibers and germline BAP1 mutations.[1,2]. GI, gastrointestinal; HMGB1, high-mobility group box 1; MEF, mouse embryonic fibroblast; MM, malignant mesothelioma; NSAID, nonsteroidal anti-inflammatory drug; SA, salicylic acid; SCID, severe-combined immunodeficient; TNF-α, tumor necrosis factor-α Received 24.3.15; revised 04.5.15; accepted 07.5.15; Edited by G Melino to carcinogenesis has been proposed in other inflammation-related malignancies.[8] Recent data indicate that HMGB1 initiates a chain of events that promotes tumor metastasis in melanoma,[9] a malignancy that shares some common molecular pathogenetic mechanisms with MM.[2] HMGB1 levels in blood are elevated in MM,[7,10] and in several other inflammation-related cancers.[11,12]. In addition to its well-known effects in reducing inflammation, and preventing platelet aggregation and related effects on cardiovascular diseases, ASA reduces the incidence, metastatic potential and mortality of colon cancer, and possibly of other solid malignancies, most of which have inflammation-mediated initiation or progression.[14,15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
