西格列汀调节FOXO3-FOXM1信号通路对肺癌细胞化疗敏感性的影响及机制研究

doi:10.3969/j.issn.1006-6233.2024.04.01

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Abstract Objective: To investigate the effect and mechanism of sitagliptin (SIT) on the chemosensitivity of lung cancer cells by regulating the forkhead box protein O3 (FOXO3) - forkhead protein M1 (FOXM1) signaling pathway. Methods: Human lung cancer cell line A549 and cisplatin (DDP) resistant cell line A549/DDP were cultured in vitro and treated with 0, 0.5, 1, 2, 3, and 4 mmol/L of SIT. CCK-8 method was applied to determine the A549 and of A549/DDP cells viability in each group to screen the optimal concentration of SIT. A549/DDP cells were randomly separated into control group, SIT (2mmoL/L) group, an si-NC group (transfected with si-NC plasmid), a SIT (2mmol/L)+si-FOXO3 (transfected with FOXO3 siRNA plasmid) group, and were treated with 0, 2, 4, 8, 16, and 32 mg/L DDP while treating with SIT and plasmid, then the CCK-8 method was applied to determine the chemotherapy resistance index of cells in each group. A549/DDP cells were randomly separated into control group, SIT (2mmol/L) group, DDP (4mg/L) group, DDP (4mg/L)+si-NC group, DDP (4mg/L)+SIT (2mmol/L) group, and a DDP (4mg/L)+SIT (2mmol/L)+si-FOXO3 group, after grouping, the CCK-8 method, clone formation assay, and flow cytometry assay were applied to determine the proliferation and apoptosis of A549/DDP cells in each group; Western blot was applied to detect the expression of A549/DDP cell proliferation (C-myc, PCNA), apoptosis {Bax, cleaved poly ADP ribose polymerase (PARP)}, drug resistance {P-glycoprotein (P-gp), multidrug resistance associated protein (MRP1), MRP2, breast cancer drug resistance protein (BCRP)} and FOXO3-FOXM1 pathway related proteins in each group. Results: Compared with the control group, the chemotherapy resistance index of cells in the SIT group decreased (P<0.05), while there was no significant change in the chemotherapy resistance index of cells in the si-NC group (P>0.05); compared with the SIT group, the SIT+si-FOXO3 group showed an increase in cell chemotherapy resistance index (P<0.05). Compared with the control group, the A549/DDP cell viability, clone formation rate, C-myc, and PCNA protein expression in the DDP group and DDP+si-NC group reduced (P<0.05), the apoptosis rate, Bax and cleaved PARP protein expression was up-regulated (P<0.05); the A549/DDP cell viability, clone formation rate, C-myc and PCNA, P-gp, MRP1, MRP2, BCRP, and FOXM1 protein expression in the DDP+SIT group reduced (P<0.05), the apoptosis rate, Bax and cleaved PARP, FOXO3 protein expression was up-regulated (P<0.05); the P-gp, MRP1, MRP2, BCRP, and FOXM1 protein expression in A549/DDP cells in the SIT group decreased (P<0.05), the FOXO3 protein expression was up-regulated (P<0.05). Compared with the DDP group, the A549/DDP cell viability, clone formation rate, C-myc and PCNA, P-gp, MRP1, MRP2, BCRP, and FOXM1 protein expression in the DDP+SIT group reduced (P<0.05), the apoptosis rate, Bax and cleaved PARP, FOXO3 protein expression was up-regulated (P<0.05); there was no significant change in all indicators of A549/DDP cells in the DDP+si-NC group (P>0.05). Compared with the DDP+SIT group, the A549/DDP cell viability, clone formation rate, C-myc and PCNA, P-gp, MRP1, MRP2, BCRP, and FOXM1 protein expression in the DDP+SIT+si-FOXO3 group increased (P<0.05), the apoptosis rate, Bax and cleaved PARP, FOXO3 protein expression decreased (P<0.05). Conclusion: SIT can down-regulate the expression of drug resistant proteins, and enhance the chemotherapy sensitivity of lung cancer cells by promoting FOXO3-FOXM1 signaling, and thereby enhance the killing effect of DDP on DDP resistant lung cancer cells.

Key words： Lung cancer Sitagliptin FOXO3-FOXM1 Chemotherapy sensitivity

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http://www.hbyxzzs.cn/EN/10.3969/j.issn.1006-6233.2024.04.01 OR http://www.hbyxzzs.cn/EN/Y2024/V30/I4/529

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