HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma.

Laura Pellegrini,Michele Carbone,Vishal S Negi,Haining Yang,Paul Morris,Harvey I Pass,Andrea Napolitano,Zeyana Salim Saad-Jube,Jiaming Xue,Kelly H Forest,David Larson,Marco E Bianchi,Giovanni Gaudino,Sandro Jube,Ian Pagano,Sandra Pastorino

doi:10.18632/oncotarget.15152

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.

Highlights

Human malignant mesothelioma (MM) is a rare, very aggressive cancer that arises from the transformation of the mesothelial cells lining the pleural, peritoneal and pericardial cavities [1]
Cells were treated with Ethyl pyruvate (EP), and after 48 hours a significantly lower amount of High-Mobility Group Box-1 protein (HMGB1) was detected in the cell culture medium, compared to vehicle-treated control cells (Figure 1A, 1B)
We observed an accumulation of HMGB1 in the nuclear fraction, in both MM cell cultures treated with EP (Figure 1C, 1D)

Summary

Introduction

Human malignant mesothelioma (MM) is a rare, very aggressive cancer that arises from the transformation of the mesothelial cells lining the pleural, peritoneal and pericardial cavities [1]. MM causes about 43,000 deaths per year worldwide, and, in the United States, approximately 3,200 individuals are diagnosed annually with MM [1, 2]. The chronic inflammation caused by asbestos deposition in tissues, leads to TNF-α release, which promotes tumor development [6, 7]. We recently discovered that BAP1 germline mutations play a critical role in MM pathogenesis [8, 9]. Somatic mutations in the BAP1 gene are frequent in sporadic MM [10,11,12]. The median overall survival is less than a year for patients with pleural MM, and a 5-year survival is observed in approximately 10% of patients diagnosed at early stages [1]. The development and evaluation of new therapeutic approaches is highly needed

Methods

Results

Conclusion