STAT3 but Not HIF-1 Is Important in Mediating Hypoxia-Induced Chemoresistance in MDA-MB-231, a Triple Negative Breast Cancer Cell Line

被引:35
作者
Abyaneh, Hoda Soleymani [1 ]
Gupta, Nidhi [2 ]
Radziwon-Balicka, Aneta [1 ]
Jurasz, Paul [1 ]
Seubert, John [1 ]
Lai, Raymond [2 ,3 ,4 ]
Lavasanifar, Afsaneh [1 ,5 ]
机构
[1] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2E1, Canada
[2] Univ Alberta, Dept Lab Med & Pathol, Edmonton, AB T6G 2E1, Canada
[3] Univ Alberta, Dept Oncol, Edmonton, AB T6G 2E1, Canada
[4] DynaLIFEDx Med Labs, Edmonton, AB T5J 5E2, Canada
[5] Univ Alberta, Dept Chem & Mat Engn, Fac Engn, Edmonton, AB T6G 1H9, Canada
基金
加拿大健康研究院;
关键词
hypoxia-induced chemoresistance; HIF-1; STAT3; cisplatin; cancer stemness; CISPLATIN RESISTANCE; DRUG-RESISTANCE; DOWN-REGULATION; SIGNAL TRANSDUCER; ABC TRANSPORTERS; VEGF EXPRESSION; UP-REGULATION; LUNG-CANCER; APOPTOSIS; CONTRIBUTES;
D O I
10.3390/cancers9100137
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Hypoxia-induced chemoresistance (HICR) is a well-recognized phenomenon, and in many experimental models, hypoxia inducible factor-1 (HIF-1) is believed to be a key player. We aimed to better understand the mechanism underlying HICR in a triple negative breast cancer cell line, MDA-MB-231, with a focus on the role of HIF-1. In this context, the effect of hypoxia on the sensitivity of MDA-MB-231 cells to cisplatin and their stem-like features was evaluated and the role of HIF-1 in both phenomena was assessed. Our results showed that hypoxia significantly increased MDA-MB-231 resistance to cisplatin. Correlating with this, intracellular uptake of cisplatin was significantly reduced under hypoxia. Furthermore, the stem-like features of MDA-MB-231 cells increased as evidenced by the significant increases in the expression of ATP-binding cassette (ABC) drug transporters, the proportion of CD44(+)/CD24(-) cells, clonogenic survival and cisplatin chemoresistance. Under hypoxia, both the protein level and DNA binding of HIF-1 was dramatically increased. Surprisingly, siRNA knockdown of HIF-1 did not result in an appreciable change to HICR. Instead, signal transducer and activator of transcription 3 (STAT3) activation was found to be important. STAT3 activation may confer HICR by upregulating ABC transporters, particularly ABCC2 and ABCC6. This study has demonstrated that, in MDA-MB-231 cells, STAT3 rather than HIF-1 is important in mediating HICR to cisplatin.
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页数:17
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