Abstract
Lung cancer is one of the most common malignant tumor types globally. Acquisition of chemoresistance in lung cancer cells is the primary cause of chemotherapy failure. Inflammatory chemokine C-C motif chemokine ligand 2 (CCL2) has been reported to be involved in the progression of cancer and drug resistance. However, its function in docetaxel (DTX) resistance of lung cancer remains unclear. In the present study, the mechanism underlying DTX-induced drug resistance was investigated. Reverse transcription-quantitative polymerase chain reaction and western blot analysis revealed that DTX treatment increased the mRNA and protein expression of CCL2 in lung cancer A549 cells. CCL2 was knocked down by small interfering RNA or was overexpressed by recombinant CCL2 lentivirus, and cell viability was determined. An MTT assay indicated that CCL2 downregulation decreased the viability of A549 cells and augmented the DTX-induced cytotoxicity, whereas CCL2 upregulation protected A549 cells from DTX-induced cytotoxicity. Additionally, it was revealed that CCL2 overexpression activated phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling and inhibited apoptosis-associated protein caspase-3 activation and B-cell lymphoma 2 (Bcl-2) phosphorylation at Ser70 induced by DTX, and enhanced DTX-induced Bcl-2-associated death promoter phosphorylation at Ser112. PI3K/AKT inhibitor LY294002 restored DTX-induced caspase-3 activation and Bcl-2 phosphorylation, reversed the effect of CCL2 on the viability of A549 cells and enhanced DTX-induced cytotoxicity. These results demonstrated that chemoresistance may be mediated by cell stress responses involving CCL2 expression, suggesting that CCL2 may be a potential target for enhancing the therapeutic effect of DTX in lung cancer.