PI3K/Akt/NF-κB regulate ABCB1/P-glycoprotein-mediated multidrug resistance in colon carcinoma cells
10.3969/j.issn.1007-3969.2014.02.005
- VernacularTitle:PI3K/Akt/NF-κB通路调控ABCB1/P-gp介导的人结肠癌细胞多药耐药的研究
- Author:
Hua SUI
;
Xiaoling FU
;
Shufang PAN
;
Xiaolan SHI
;
Baohui JIN
;
Huirong ZHU
;
Jianlin REN
;
Qi LI
- Publication Type:Journal Article
- Keywords:
Colon carcinoma;
Multidrug-resistance;
P-glycoprotein;
Phosphoinositide 3-kinases (PI3K);
Nuclear factor kappa-light-chain-enhancer of activated B (NF-κB)
- From:
China Oncology
2014;(2):106-111
- CountryChina
- Language:Chinese
-
Abstract:
Background and purpose: Multidrug resistance (MDR) is the dominating obstacle to the chemotherapy. There is strong evidence that the phosphoinositide 3-kinases (PI3Ks) signaling pathway is involved in MDR phenotype, however, the mechanism of MDR occurrence is still unknown. This study tended to investigate the regulating effect of PI3K/Akt signaling pathway and its downstream target genes in P-glycoprotein (P-gp) (ABCB1 gene encoding)-mediated MDR in human colon carcinoma HCT-116/L-OHP cells. Methods:Pretreatment with PI3K selective inhibitor LY294002 (20μmol/L) for 2 h, the sensitivity of L-OHP was evaluated by the CCK-8 (cell counting kit-8) assay in HCT-116/L-OHP cells, and the expressions of P-gp, LRP, MRP-2, Akt, p-Akt, IκB and p-IκB were evaluated by Western blot. The activity of ABCB1 promoter was evaluated by chromatin immunoprecipitation analysis (CHIP). Results: After inhibiting the activity of PI3K/Akt signaling pathway, the IC50 value of L-OHP decreased from(157.48±16.73)μg/mL to (53.68±3.18)μg/mL in HCT-116/L-OHP cells, and the reversal index was 2.93 (P<0.01). The expressions of P-gp, p-Akt and p-IκB were down-regulation compared with the concrol group (P<0.01), but the expressions of LRP, MRP-2, Akt and IκB didn't change signiifcantly. CHIP result has conifrmed that NF-κB protein could bind to the region of ABCB1 gene promoter in HCT116/L-OHP cells. Conclusion:Blocking of PI3K/Akt/NF-kB signal pathway could increase the drug sensitivity to MDR cells, inhibit the phosphorylation of p-Akt and p-IκB, and reversing ABCB1/P-glycoprotein-mediated multidrug resistance in colon carcinoma cells.
