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Implantation and Monitoring by PET/CT of an Orthotopic Model of Human Pleural Mesothelioma in Athymic Mice
Published on: December 21, 2019
HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma
Laura Pellegrini1, Jiaming Xue1,2, David Larson1
1University of Hawai'i Cancer Center, University of Hawai'i at Manoa, Honolulu, HI, USA.
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.
Insights
Ethyl pyruvate (EP) effectively inhibits malignant mesothelioma (MM) by reducing High-Mobility Group Box-1 protein (HMGB1) secretion. This novel therapeutic approach hampers cancer cell growth and tumor progression in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Malignant mesothelioma (MM) is an aggressive cancer strongly associated with asbestos and erionite exposure.
- High-Mobility Group Box-1 protein (HMGB1) is a key driver of MM development and progression.
- Previous studies demonstrated HMGB1 inhibition's therapeutic potential in MM.
Purpose of the Study:
- To investigate the efficacy of Ethyl pyruvate (EP) as an HMGB1 inhibitor in malignant mesothelioma.
- To evaluate EP's impact on MM cell phenotype in vitro and tumor growth in vivo.
Main Methods:
- Tissue culture studies of MM cells treated with EP.
- Orthotopic MM xenograft model in mice to assess in vivo efficacy.
- Analysis of HMGB1 secretion, RAGE expression, and NF-κB activation.
- Measurement of MM cell motility, proliferation, and anchorage-independent growth.
Main Results:
- EP significantly reduced HMGB1 secretion by MM cells, leading to decreased RAGE expression and NF-κB activation.
- EP impaired MM cell motility, proliferation, and anchorage-independent growth in vitro.
- EP treatment lowered serum HMGB1 levels in mice and inhibited MM xenograft tumor growth.
Conclusions:
- Ethyl pyruvate effectively targets the malignant phenotype of mesothelioma by inhibiting HMGB1.
- EP demonstrates significant therapeutic potential for malignant mesothelioma patients.
- This study offers a novel therapeutic strategy for this aggressive cancer.
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