HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma

// Laura Pellegrini 1 , Jiaming Xue 1, 3 , David Larson 1 , Sandra Pastorino 1 , Sandro Jube 2 , Kelly H. Forest 3 , Zeyana Salim Saad-Jube 4 , Andrea Napolitano 1, 5 , Ian Pagano 1 , Vishal S. Negi 5 , Marco E. Bianchi 6 , Paul Morris 7 , Harvey I. Pass 8 , Giovanni Gaudino 1 , Michele Carbone 1 , Haining Yang 1 1 University of Hawai'i Cancer Center, University of Hawai'i at Manoa, Honolulu, HI, USA 2 University of Hawai'i at Manoa, Department of Cell and Molecular Biology, John A. Burns School of Medicine, Honolulu, HI, USA 3 Leeward Community College, Mathematics and Sciences Division, University of Hawai'i System, Pearl City, HI, USA 4 University of Hawai'i at Manoa, Myron B. Thompson School of Social Work, Office of Public Health and Center on Aging, Honolulu, HI, USA 5 University of Hawai'i at Manoa, Department of Molecular Biosciences and Bioengineering, Honolulu, HI, USA 6 San Raffaele University and Research Institute, Milan, Italy 7 Department of Thoracic Surgery, Queen's Medical Center, Honolulu, HI, USA 8 New York University School of Medicine, Department of Cardiothoracic Surgery, New York, NY, USA Correspondence to: Haining Yang, email: hyang@cc.hawaii.edu Michele Carbone, email: mcarbone@cc.hawaii.edu Keywords: HMGB1, RAGE, ethyl pyruvate, mesothelioma, therapeutic Received: June 30, 2016      Accepted: January 23, 2017      Published: February 07, 2017 ABSTRACT 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-κB 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.