title: HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma.
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.
authors.affiliation: University of Hawai'i Cancer Center, University of Hawai'i at Manoa, Honolulu, HI, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Pellegrini
authors.affiliation: University of Hawai'i Cancer Center, University of Hawai'i at Manoa, Honolulu, HI, USA.|Leeward Community College, Mathematics and Sciences Division, University of Hawai'i System, Pearl City, HI, USA.
authors.forename: Jiaming
authors.initials: J
authors.lastname: Xue
authors.affiliation: University of Hawai'i Cancer Center, University of Hawai'i at Manoa, Honolulu, HI, USA.
authors.forename: David
authors.initials: D
authors.lastname: Larson
authors.affiliation: University of Hawai'i Cancer Center, University of Hawai'i at Manoa, Honolulu, HI, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pastorino
authors.affiliation: University of Hawai'i at Manoa, Department of Cell and Molecular Biology, John A. Burns School of Medicine, Honolulu, HI, USA.
authors.forename: Sandro
authors.initials: S
authors.lastname: Jube
authors.affiliation: Leeward Community College, Mathematics and Sciences Division, University of Hawai'i System, Pearl City, HI, USA.
authors.forename: Kelly H
authors.initials: KH
authors.lastname: Forest
authors.affiliation: University of Hawai'i at Manoa, Myron B. Thompson School of Social Work, Office of Public Health and Center on Aging, Honolulu, HI, USA.
authors.forename: Zeyana Salim
authors.initials: ZS
authors.lastname: Saad-Jube
authors.affiliation: University of Hawai'i Cancer Center, University of Hawai'i at Manoa, Honolulu, HI, USA.|University of Hawai'i at Manoa, Department of Molecular Biosciences and Bioengineering, Honolulu, HI, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Napolitano
authors.affiliation: University of Hawai'i Cancer Center, University of Hawai'i at Manoa, Honolulu, HI, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Pagano
authors.affiliation: University of Hawai'i at Manoa, Department of Molecular Biosciences and Bioengineering, Honolulu, HI, USA.
authors.forename: Vishal S
authors.initials: VS
authors.lastname: Negi
authors.affiliation: San Raffaele University and Research Institute, Milan, Italy.
authors.forename: Marco E
authors.initials: ME
authors.lastname: Bianchi
authors.affiliation: Department of Thoracic Surgery, Queen's Medical Center, Honolulu, HI, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Morris
authors.affiliation: New York University School of Medicine, Department of Cardiothoracic Surgery, New York, NY, USA.
authors.forename: Harvey I
authors.initials: HI
authors.lastname: Pass
authors.affiliation: University of Hawai'i Cancer Center, University of Hawai'i at Manoa, Honolulu, HI, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gaudino
authors.affiliation: University of Hawai'i Cancer Center, University of Hawai'i at Manoa, Honolulu, HI, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Carbone
authors.affiliation: University of Hawai'i Cancer Center, University of Hawai'i at Manoa, Honolulu, HI, USA.
authors.forename: Haining
authors.initials: H
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008654:Mesothelioma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009367:Neoplasm Staging; D011379:Prognosis; D011773:Pyruvates / Q000494:pharmacology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D011773:Pyruvates; C046522:ethyl pyruvate
keywords: HMGB1; RAGE; ethyl pyruvate; mesothelioma; therapeutic