Blockade of HMGB1 signaling pathway by ethyl pyruvate inhibits tumor growth in diffuse large B-cell lymphoma.

Abstract

High mobility group box 1 (HMGB1) protein in the tumor microenvironment actively contributes to tumor progression but its role in diffuse large B-cell lymphoma (DLBCL) is unknown. The aim of this study was to determine the mechanism by which HMGB1 promotes tumor growth in DLBCL and whether blockade of HMGB1 signaling pathway could inhibit tumorigenesis. We report that HMGB1 promotes proliferation of DLBCL cells by activation of AKT, extracellular signal-regulated kinases 1/2 (ERK1/2), signal transducer and activator of transcription 3 (STAT3) and SRC Proto-Oncogene, Non-Receptor Tyrosine Kinase (Src). Ethyl pyruvate (EP), an anti-inflammatory agent, inhibits HMGB1 active release from DLBCL cells and significantly inhibited proliferation of DLBCL cells in vitro. Treatment with EP significantly prevented and inhibited tumor growth in vivo and prolonged DLBCL-bearing mice survival. EP significantly downregulated HMGB1 expression and phosphorylation of Src and ERK1/2 in mice lymphoma tissue. EP induced accumulation of the cell cycle inhibitor p27 but downregulated expression of cyclin-dependent kinase 2 (CDK2). Increased nuclear translocation of p27 interacted with CDK2 and cyclin A, which led to blockade of cell cycle progression at the G1 to S phase transition. In conclusion, we demonstrated for the first time that blockade of HMGB1-mediated signaling pathway by EP effectively inhibited DLBCL tumorigenesis and disease progression.

• Authors: Tian Zhang, Xu-Wen Guan, John G Gribben, Feng-Ting Liu, Li Jia
• Journal: Cell death & disease (Cell Death Dis) Vol. 10 Issue 5 Pg. 330 (04 15 2019) ISSN: 2041-4889 [Electronic] England
• PMID: 30988279 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• HMGB1 Protein
• MAS1 protein, human
• Proto-Oncogene Mas
• Pyruvates
• STAT3 Transcription Factor
• ethyl pyruvate
• Cyclin-Dependent Kinase Inhibitor p27
• src-Family Kinases
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase Inhibitor p27 (metabolism)
• Female
• G1 Phase Cell Cycle Checkpoints (drug effects)
• HMGB1 Protein (metabolism)
• Humans
• Lymphoma, Large B-Cell, Diffuse (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Phosphorylation (drug effects)
• Proto-Oncogene Mas
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyruvates (pharmacology, therapeutic use)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• src-Family Kinases (metabolism)