Involvement of hypoxia-inducible factor-1α in the mechanism of multidrug resistance phenotype in gastric cancer

Abstract

Objective To investigate the potential mechanism of multidrug resistance phenotype in gastric cancer cell line SGC7901/DDP mediated by hyposia-induced factor 1α (HIF-1α). Methods A resistant cell line SGC7901/DDP with the MDR and MRP4 phenotype was established by increasingly dose of cisplatin from 0.02 to 1.00 mg/L during 10 months. The HIF-1α expression was blocked by the HIF-1α inhibitor YC-1 in both the drug-sensitive cell line SGC7901 and the DDP-resistant cell hne SGC7901/ DDP. The drug sensitivity was tested by MTT assay,cell apoptosis rate by flow cytometry, and the expres-sion of HIF-1α and the multidrug-resistant protein P-glycoprotein (P-gp) by RT-PCR and Western blot in both the mRNA and protein levels. Results The inhibition of HIF-1α by YC-1 resulted in the increased drug sensitivity of SGC7901/DDP cell line, with IC50 of DDP decreased from (52. 175 ± 6. 163) mg/L to (11. 078± 3. 645) mg/L (P ＜ 0. 01) and cell apoptosis rate increased from 1.03% to 14. 26% (P ＜0. 01). And the down-regulation of HIF-1α and P-gp of SGC7901/DDP cell line was greatly decreased from 1. 846±0. 135 and 2. 017±0. 102 to 0. 814±0.057 and 0. 962±0. 039 respectively in both mRNA and protein levels (P ＜0.01). Conclusion The HIF-1α mediated DDP-resistant phenotype through P-gp expression and anti-apoptosis signal pathway in gastric cancer,which would be a novel and promising target gene for reversing MDR. Key words: Gastric carcinoma; Multidrug resistance; P-glyeoprotein; HIF-1α