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Signal transducer and activator of transcription 3 and 5 regulate system Xc- and redox balance in human breast cancer cells

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Abstract

System Xc- is a cystine/glutamate antiporter that contributes to the maintenance of cellular redox balance. The human xCT (SLC7A11) gene encodes the functional subunit of system Xc-. Transcription factors regulating antioxidant defense mechanisms including system Xc- are of therapeutic interest, especially given that aggressive breast cancer cells exhibit increased system Xc- function. This investigation provides evidence that xCT expression is regulated by STAT3 and/or STAT5A, functionally affecting the antiporter in human breast cancer cells. Computationally analyzing two kilobase pairs of the xCT promoter/5′ flanking region identified a distal gamma-activated site (GAS) motif, with truncations significantly increasing luciferase reporter activity. Similar transcriptional increases were obtained after treating cells transiently transfected with the full-length xCT promoter construct with STAT3/5 pharmacological inhibitors. Knock-down of STAT3 or STAT5A with siRNAs produced similar results. However, GAS site mutation significantly reduced xCT transcriptional activity, suggesting that STATs may interact with other transcription factors at more proximal promoter sites. STAT3 and STAT5A were bound to the xCT promoter in MDA-MB-231 cells, and binding was disrupted by pre-treatment with STAT inhibitors. Pharmacologically suppressing STAT3/5 activation significantly increased xCT mRNA and protein levels, as well as cystine uptake, glutamate release, and total levels of intracellular glutathione. Our data suggest that STAT proteins negatively regulate basal xCT expression. Blocking STAT3/5-mediated signaling induces an adaptive, compensatory mechanism to protect breast cancer cells from stress, including reactive oxygen species, by up-regulating xCT expression and the function of system Xc-. We propose that targeting system Xc- together with STAT3/5 inhibitors may heighten therapeutic anti-cancer effects.

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Acknowledgments

The authors thank Jennifer Fazzari for helping to trouble-shoot aspects related to cloning the human xCT promoter construct and critical feedback on the manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

Funding

KLM is supported by a Canadian Breast Cancer Foundation (CBCF) fellowship, and the research of GS is funded by grants from the CBCF and Canadian Institutes of Health Research (CIHR). The research of PG, a Canada Research Chair, is funded by CBCF, CIHR, and Canadian Foundation for Innovation grants.

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  1. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, L8S 4L8, Canada

    Katja Linher-Melville & Gurmit Singh

  2. Department of Chemical and Physical Sciences, University of Toronto at Mississauga, Mississauga, ON, L5L 1C6, Canada

    Sina Haftchenary & Patrick Gunning

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  1. Katja Linher-Melville
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Linher-Melville, K., Haftchenary, S., Gunning, P. et al. Signal transducer and activator of transcription 3 and 5 regulate system Xc- and redox balance in human breast cancer cells. Mol Cell Biochem 405, 205–221 (2015). https://doi.org/10.1007/s11010-015-2412-4

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