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Mechanism of sunitinib inducing NKG2DLs expressions in multidrug resistant nasopharyngeal carcinoma CNE2/DDP cells
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Abstract:
Objective: To investigate the mec hanism by which unitinib induces upregulation of NKG2D ligands(NKG2DLs) expressions in nasopharyngeal carcinoma CNE2/DDP cells with high or low ABCG2 expression (ABCG2highCNE2/DDP cells or ABCG2lowCNE2/DDP cells). Methods: Caspase8 activity and mitochondrial membrane potential were detected by caspase8 activity kit and mitochondrial membrane potential assay kit in ABCG2highCNE2/DDP cells or ABCG2low CNE2/DDP cells after cocultured with NK cells. Expressions of signal molecules involved in DNA damage and repair system were detected by RTPCR in ABCG2highCNE2/DDP cells and ABCG2lowCNE2/DDP cells before and after sunitinib treatment. Results: Caspase8 activities in ABCG2highCNE2/DDP cells and ABCG2lowCNE2/DDP cells were ignificantly increased after cocultured with in NK cells. After treatment with sunitinib, caspase8 activities in the co culture system were 1-1.5 times higher than those in the untreated ABCG2high and ABCG2lowCNE2/DDP cells (P<0.01). Sunitinib inhibited mitochondrial membrane potentials of ABCG2high and ABCG2lowCNE2/DDP cells in NK cell coculture systems, with the potentials in two kinds of sunitinibtreated CNE2/DDP cells decreased to (76.58±2.32)% and (73.11±1.93)%, respectively, which were markedly lower than those in the untreated ABCG2high and ABCG2low CNE2/DDP cells (P<0.05). Sunitinib could increase mRNA expressions of ATR, CHK1 and CHK2 in ABCG2high and ABCG2 lowCNE2/DDP cells, and induce P53 and NFκB mRNA expressions. Conclusion: Sunitinib can upregulate NKG2DLs expressions in CNE2/DDP cells by activating signaling molecules related to DNA damage and repair system and NFκB, and enhance NK cellinduced apoptosis of tumor cells through death receptor and mitochondrial pathways.
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Project Supported:
Project supported by the National Natural Science Foundation of China (No. 30973454), and the Key Program of Natural Science Foundation of Guangdong Province (No. 9251051501000007)
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