Lactate Induces Production of the tRNAHis Half to Promote B-lymphoblastic Cell Proliferation.
Mol Ther
; 28(11): 2442-2457, 2020 11 04.
Article
in En
| MEDLINE
| ID: mdl-32966775
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
RNA, Transfer, His
/
B-Lymphocytes
/
Lactic Acid
/
RNA, Small Untranslated
Type of study:
Etiology_studies
/
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Mol Ther
Journal subject:
BIOLOGIA MOLECULAR
/
TERAPEUTICA
Year:
2020
Type:
Article