Augmenter of liver regeneration promotes drug resistance of acute lymphoblastic leukemia through the alteration of mitochondrial functions and the inhibition of the mitochondrial apoptosis pathway
Jingwen Zhou and Ying Zhou contributed equally to this work.
Abstract
Background
Acute T lymphoblastic leukemia (T-ALL) occurs in 25% of adults diagnosed with Acute lymphocytic leukemia (ALL), and drug resistance is still a clinical obstacle. Augmenter of liver regeneration (ALR) is important to ALL drug resistance and is involved in the regulation of mitochondrial function; we speculated that the high expression of ALR in T-ALL promotes drug resistance through the alteration of mitochondrial function and the inhibition of the mitochondrial apoptosis pathway.
Method
We silenced and overexpressed ALR in the T-ALL cell lines that were untreated or treated with dexamethasone (DXM) or methotrexate (MTX). Apoptosis, proliferation, reactive oxygen species and ATP productions, mitochondrial membrane potential, and mitochondrial respiratory chain complex expression in cells were examined. The data were collated to comprehensively evaluate the effects of ALR expression change on mitochondrial function and drug resistance in T-ALL cells.
Results
ALR knockdown led to the inhibition of proliferation, an increase in apoptosis, and the promotion of the cells' sensitivity to drugs. It also showed mitochondrial dysfunction. ALR knockdown actived the mitochondrial apoptosis pathway. The treatment of ALR knockdown T-ALL cells with MTX or DXM further altered the mitochondrial function of T-ALL cells and actived the mitochondrial apoptosis pathway. Overexpression of ALR promoted cell proliferation and drug resistance, reduced apoptosis, protected mitochondrial function, and inhibited the mitochondrial apoptosis pathway.
Conclusion
T-ALL resistance caused by ALR through the alteration of mitochondrial function is associated with the inhibition of the mitochondrial apoptosis pathway.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author, Yan Shen, upon reasonable request.
