Effect and Mechanism of Atorvastatin on Reversing Drug Resistance in Leukemia by Regulating Glycolysis through PTEN/mTOR Pathway.
10.19746/j.cnki.issn.1009-2137.2023.01.006
- Author:
Miao LIU
1
;
Pan ZHOU
2
Author Information
1. Department of Paediatrics, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China.E-mail: liumiao915@163.com.
2. Hubei Medical Devices Quality Supervision and Test Institute, Wuhan 430075, Hubei Province, China.
- Publication Type:Journal Article
- Keywords:
PTEN/mTOR pathway;
atorvastatin;
glycolysis;
leukemia drug resistance
- MeSH:
Humans;
Atorvastatin/pharmacology*;
PTEN Phosphohydrolase/pharmacology*;
Sincalide/metabolism*;
Drug Resistance, Neoplasm/genetics*;
TOR Serine-Threonine Kinases/metabolism*;
Leukemia, Promyelocytic, Acute/drug therapy*;
Doxorubicin/pharmacology*;
Apoptosis;
RNA, Small Interfering/pharmacology*;
Glycolysis;
Glucose/therapeutic use*;
Cell Proliferation
- From:
Journal of Experimental Hematology
2023;31(1):38-44
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE:To investigate the influence and mechanism of atorvastatin on glycolysis of adriamycin resistant acute promyelocytic leukemia (APL) cell line HL-60/ADM.
METHODS:HL-60/ADM cells in logarithmic growth phase were treated with different concentrations of atorvastatin, then the cell proliferation activity was measured by CCK-8 assay, the apoptosis was detected by flow cytometry, the glycolytic activity was checked by glucose consumption test, and the protein expressions of PTEN, p-mTOR, PKM2, HK2, P-gp and MRP1 were detected by Western blot. After transfection of PTEN-siRNA into HL-60/ADM cells, the effects of low expression of PTEN on atorvastatin regulating the behaviors of apoptosis and glycolytic metabolism in HL-60/ADM cells were further detected.
RESULTS:CCK-8 results showed that atorvastatin could inhibit the proliferation of HL-60/ADM cells in a concentration-dependent and time-dependent manner (r=0.872, r=0.936), and the proliferation activity was inhibited most significantly when treated with 10 μmol/L atorvastatin for 24 h, which was decreased to (32.3±2.18)%. Flow cytometry results showed that atorvastatin induced the apoptosis of HL-60/ADM cells in a concentration-dependent manner (r=0.796), and the apoptosis was induced most notably when treated with 10 μmol/L atorvastatin for 24 h, which reached to (48.78±2.95)%. The results of glucose consumption test showed that atorvastatin significantly inhibited the glycolytic activity of HL-60/ADM cells in a concentration-dependent and time-dependent manner (r=0.915, r=0.748), and this inhibition was most strikingly when treated with 10 μmol/L atorvastatin for 24 h, reducing the relative glucose consumption to (46.53±1.71)%. Western blot indicated that the expressions of p-mTOR, PKM2, HK2, P-gp and MRP1 protein were decreased in a concentration-dependent manner (r=0.737, r=0.695, r=0.829, r=0.781, r=0.632), while the expression of PTEN protein was increased in a concentration-dependent manner (r=0.531), when treated with different concentrations of atorvastatin for 24 h. After PTEN-siRNA transfected into HL-60/ADM cells, it showed that low expression of PTEN had weakened the promoting effect of atorvastatin on apoptosis and inhibitory effect on glycolysis and multidrug resistance.
CONCLUSION:Atorvastatin can inhibit the proliferation, glycolysis, and induce apoptosis of HL-60/ADM cells. It may be related to the mechanism of increasing the expression of PTEN, inhibiting mTOR activation, and decreasing the expressions of PKM2 and HK2, thus reverse drug resistance.
