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Cancers 2017, 9(10), 137; https://doi.org/10.3390/cancers9100137

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

1
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada
2
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2E1, Canada
3
Department of Oncology, University of Alberta, Edmonton, AB T6G 2E1, Canada
4
DynaLIFEDx Medical Laboratories, Edmonton, AB T5J 5E2, Canada
5
Department of Chemical & Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB T6G 1H9, Canada
*
Authors to whom correspondence should be addressed.
Received: 10 September 2017 / Revised: 2 October 2017 / Accepted: 10 October 2017 / Published: 14 October 2017
(This article belongs to the Special Issue Drug Resistance in Cancers)
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Abstract

Hypoxia-induced chemoresistance (HICR) is a well-recognized phenomenon, and in many experimental models, hypoxia inducible factor-1α (HIF-1α) 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-1α. 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-1α 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-1α was dramatically increased. Surprisingly, siRNA knockdown of HIF-1α 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-1α is important in mediating HICR to cisplatin. View Full-Text
Keywords: hypoxia-induced chemoresistance; HIF-1α; STAT3; cisplatin; cancer stemness hypoxia-induced chemoresistance; HIF-1α; STAT3; cisplatin; cancer stemness
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Soleymani Abyaneh, H.; Gupta, N.; Radziwon-Balicka, A.; Jurasz, P.; Seubert, J.; Lai, R.; Lavasanifar, A. STAT3 but Not HIF-1α Is Important in Mediating Hypoxia-Induced Chemoresistance in MDA-MB-231, a Triple Negative Breast Cancer Cell Line. Cancers 2017, 9, 137.

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