Journal
ONCOTARGET
Volume 8, Issue 14, Pages 22649-22661Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.15152
Keywords
HMGB1; RAGE; ethyl pyruvate; mesothelioma; therapeutic
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Funding
- DOD [CA120355]
- Riviera United 4-a Cure and Shino-Test Corporation
- University of Hawai'i Foundation
- Honeywell International Inc
- [NCI-R01 CA160715]
- [NCI-R01 CA198138-01]
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Human malignant mesothelioma (MM) is an aggressive cancer linked to asbestos and erionite exposure. We previously reported that High-Mobility Group Box-1 protein (HMGB1), a prototypic damage-associated molecular pattern, drives MM development and sustains MM progression. Moreover, we demonstrated that targeting HMGB1 inhibited MM cell growth and motility in vitro, reduced tumor growth in vivo, and prolonged survival of MM-bearing mice. Ethyl pyruvate (EP), the ethyl ester of pyruvic acid, has been shown to be an effective HMGB1 inhibitor in inflammation-related diseases and several cancers. Here, we studied the effect of EP on the malignant phenotype of MM cells in tissue culture and on tumor growth in vivo using an orthotopic MM xenograft model. We found that EP impairs HMGB1 secretion by MM cells leading to reduced RAGE expression and NF-kappa B activation. As a consequence, EP impaired cell motility, cell proliferation, and anchorage-independent growth of MM cells. Moreover, EP reduced HMGB1 serum levels in mice and inhibited the growth of MM xenografts. Our results indicate that EP effectively hampers the malignant phenotype of MM, offering a novel potential therapeutic approach to patients afflicted with this dismal disease.
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