Objectives: The high frequency of chemotherapy resistance is ultimately responsible for clinical relapse in acute lymphoblastic leukemia (ALL). Nevertheless, the molecular mechanism relevant to glucocorticoid (GC) resistance remains ambiguous.
Methods: Quantitative real-time polymerase chain reaction and Western blot were performed to detect the expressions of paraoxonase 2 (PON2), Bcl-2 and Bax. shRNA was used to knockdown PON2 expression in SUP-B15 and REH cell. CCK-8 and flow cytometry assay were conducted to monitor the changes of proliferation and apoptosis in ALL cells. The growth of ALL REH cells in vivo was determined using transplanted tumor model.
Results: This study was designed to identify GC resistance-associated genes by means of the transcriptome chip from the public Gene Expression Omnibus database, and preliminarily investigation of dexamethasone (DEX)-resistance mechanism in ALL. We disclosed that PON2 expression was elevated in ALL patients and especially higher in DEX-resistance ALL patients. Then, cell apoptosis assay suggested that silencing of PON2 dramatically promoted in DEX-resistant ALL cells apoptosis and the activity of Caspase 3 induced by DEX administration. In xenograft tumor model, PON2 knockdown significantly reduced DEX-resistant ALL cells growth in immunodeficient mice.
Conclusions: Collectively, inhibition of PON2 may represent a novel method to restore the sensitivity of treatment-resistant ALL to GC-induced cell death.
Keywords: ALL; GEO; PON2; apoptosis; dexamethasone; glucocorticoid; resistance; xenograft.