Blockage of bone marrow kinase in chromosome X enhances ABC294640-induced growth inhibition and apoptosis of colorectal cancer cells
Purpose: To investigate the role of bone marrow kinase in chromosome X (BMX) in colorectal cancer (CRC) cell resistance to ABC294640 treatment.
Methods: HCT-116R, LS174T and WiDr cells were transfected with either BMX-specific siRNA or scrambled siRNA, and then BMX mRNA and protein expressions were detected by quantitative polymerase chain reaction (qPCR) and western blotting, respectively. The cells were treated with ABC294640 and cell viability evaluated using cell counting and colony formation assays. Apoptosis was
determined by detecting caspase 3/7 activity. To evaluate tumor growth of HCT-116R cells, a xenograft model was utilized to measure tumor size.
Results: Pharmacological inhibition of sphingosine kinase type 2 (SK2) with ABC294640 significantly decreased cell viability (p < 0.001) when compared with control group. SK2 inhibition also remarkably induced apoptosis in HCT-116 CRC cells in a dose-dependent manner (p < 0.01 and p < 0.001). However, no significant effects were observed in HCT-116R, LS174T, or WiDr cells following ABC294640 treatment. BMX mRNA and protein expression increased in ABC294640-resistant cell lines. In addition, silencing BMX expression with siRNA potentiated ABC294640-induced inhibition of tumor growth in CRC cells in vitro and in vivo.
Conclusion: ABC294640-induced BMX upregulation impedes the antitumor effect of ABC294640 in CRC cells. Therefore, these results may provide a novel therapeutic strategy for CRC using a combination of ABC294640 treatment and BMX blockade.
Keywords: ABC294640, Apoptosis, Bone marrow kinase in chromosome X, Cell viability, Colorectal cancer