HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma

Laura Pellegrini, J Xue, D Larson, S Pastorino, S Jube, KH Forest, ZS Saad-Jube, A Napolitano, I Pagano, VS Negi, ME Bianchi, P Morris, HI Pass, G Gaudino, M Carbone, H Yang

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)22649-22661
Number of pages13
JournalOncotarget
Volume8
Issue number14
Publication statusPublished - 2017

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Mesothelioma
Protein Transport
Phenotype
HMGB1 Protein
Growth
Heterografts
Cell Movement
Neoplasms
ethyl pyruvate
Malignant Mesothelioma
Asbestos
Pyruvic Acid
Esters
Cell Proliferation
Inflammation

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Pellegrini, L., Xue, J., Larson, D., Pastorino, S., Jube, S., Forest, KH., ... Yang, H. (2017). HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma. Oncotarget, 8(14), 22649-22661.

HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma. / Pellegrini, Laura; Xue, J; Larson, D; Pastorino, S; Jube, S; Forest, KH; Saad-Jube, ZS; Napolitano, A; Pagano, I; Negi, VS; Bianchi, ME; Morris, P; Pass, HI; Gaudino, G; Carbone, M; Yang, H.

In: Oncotarget, Vol. 8, No. 14, 2017, p. 22649-22661.

Research output: Contribution to journalArticle

Pellegrini, L, Xue, J, Larson, D, Pastorino, S, Jube, S, Forest, KH, Saad-Jube, ZS, Napolitano, A, Pagano, I, Negi, VS, Bianchi, ME, Morris, P, Pass, HI, Gaudino, G, Carbone, M & Yang, H 2017, 'HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma', Oncotarget, vol. 8, no. 14, pp. 22649-22661.
Pellegrini L, Xue J, Larson D, Pastorino S, Jube S, Forest KH et al. HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma. Oncotarget. 2017;8(14):22649-22661.
Pellegrini, Laura ; Xue, J ; Larson, D ; Pastorino, S ; Jube, S ; Forest, KH ; Saad-Jube, ZS ; Napolitano, A ; Pagano, I ; Negi, VS ; Bianchi, ME ; Morris, P ; Pass, HI ; Gaudino, G ; Carbone, M ; Yang, H. / HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma. In: Oncotarget. 2017 ; Vol. 8, No. 14. pp. 22649-22661.
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AU - Pastorino, S

AU - Jube, S

AU - Forest, KH

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AB - 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.

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