Hypoxia-inducible factor-1 alpha contributes to hypoxia-induced chemoresistance in gastric cancer.

Hypoxia induced drug resistance is a major obstacle in the development of effective cancer therapy. Our previous study revealed that hypoxia-inducible factor-1 (HIF-1), the major transcriptional factor significantly activated by hypoxia, was overexpressed in gastric vincristine-resistant cells SGC7901/vincristine (VCR) under normoxic conditions, which suggested that it was associated with drug resistance in gastric cancer cells. In the present study, a colony-forming assay revealed that hypoxia and forced HIF-1 alpha expression increased maximal -8.9-fold or -14.8-fold of IC(50) toward vincristine in gastric cancer cell lines SGC7901 and SGC7901/VCR, respectively (P < 0.01). Annexin-V/propidium iodide staining analysis revealed hypoxia or forced HIF-1 alpha expression reduced apoptosis by 24% or 18% in SGC7901 cells (P < 0.05). Flow cytometry analysis of intracellular adriamycin revealed that hypoxia and forced expression of HIF-1 alpha increased -1.79-fold or -2.36-fold of the adriamycin releasing index, respectively (P < 0.05). However, resistance acquisition subject to hypoxia in vitro and in vivo was suppressed by blocking HIF-1 alpha expression with siRNA. We further demonstrated that HIF-1 alpha overexpression showed a 1.85-fold increased expression of Bcl-2 and a 2.16-fold decreased expression of Bax, and also showed significantly induced expression of p-gp and MRP1, which indicated that HIF-1 alpha may confer hypoxia-induced drug resistance via inhibition of drug-induced apoptosis and decreases in intracellular drug accumulation.