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.
Liu
Lili
L
State Key Laboratory of Cancer Biology, Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, 15 Changle West Road, Xi'an 710032, China.
Ning
Xiaoxuan
X
Sun
Li
L
Zhang
Hongbo
H
Shi
Yongquan
Y
Guo
Changcun
C
Han
Shuang
S
Liu
Jie
J
Sun
Shiren
S
Han
Zheyi
Z
Wu
Kaichun
K
Fan
Daiming
D
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000235:genetics; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D014750:Vincristine / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D014750:Vincristine; D051028:bcl-2-Associated X Protein; C494826:BAX protein, human; C497442:HIF1A protein, human; C421109:multidrug resistance-associated protein 1