Lactate Induces Production of the tRNAHis Half to Promote B-lymphoblastic Cell Proliferation.

Abstract

High plasma lactate is emerging as a critical regulator in development and progression of many human malignancies. Small RNAs derived from cleavage of mature tRNAs have been implicated in many cellular stresses, but the detailed mechanisms that respond to lactic acid (LA; acidic lactate) are not well defined. Here, using an Epstein-Barr virus (EBV)-immortalized B lymphoblastic cell line (LCL) as a model, we report that LA induces cleavage of mature tRNA at the anticodon loop, particularly production of three 5'-tRNA halves (5'-HisGUG, 5'-ValAAC, and 5'-GlyGCC), along with increased expression of RNA polymerase III and angiogenin (ANG). Of these, only the 5'-HisGUG half binds to the chromatin regulator argonaute-2 (AGO2) instead of the AGO1 protein for stability. Notably, the levels of ANG and 5'-HisGUG half expression in peripheral blood mononuclear cells from B cell lymphoma patients are tightly correlated with lactate dehydrogenase (LDH; a lactate indicator) in plasma. Silencing production of the 5'-HisGUG half by small interfering RNA or inhibition of ANG significantly reduces colony formation and growth of LA-induced tumor cells in vitro and in vivo using a murine xenograft model. Overall, our findings identify a novel molecular therapeutic target for the diagnosis and treatment of B cell lymphoma.

• Authors: Xiaohui Mo, Shujuan Du, Xiaoting Chen, Yuyan Wang, Xiaoqing Liu, Chongqi Zhang, Caixia Zhu, Ling Ding, Ying Li, Yin Tong, Qiang Ju, Di Qu, Fei Tan, Fang Wei, Qiliang Cai
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 28 Issue 11 Pg. 2442-2457 (11 04 2020) ISSN: 1525-0024 [Electronic] United States
• PMID: 32966775 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers
• RNA, Small Untranslated
• RNA, Transfer, His
• RNA-Binding Proteins
• Lactic Acid
• L-Lactate Dehydrogenase

Topics

• B-Lymphocytes (immunology, metabolism, pathology)
• Biomarkers
• Cell Line, Transformed
• Cell Proliferation
• Cells, Cultured
• Humans
• L-Lactate Dehydrogenase (metabolism)
• Lactic Acid (metabolism)
• Lymphoma, B-Cell (etiology, metabolism, pathology)
• Protein Binding
• RNA, Small Untranslated (genetics, metabolism)
• RNA, Transfer, His (genetics, metabolism)
• RNA-Binding Proteins (metabolism)