The glutathione peroxidase 8 (GPX8)/IL-6/STAT3 axis is essential in maintaining an aggressive breast cancer phenotype

Anees Khatib; Balakrishnan Solaimuthu; Michal Ben Yosef; Areej Abu Rmaileh; Mayur Tanna; Gidi Oren; Michal Schlesinger Frisch; Jonathan H. Axelrod; Michal Lichtenstein; Yoav D. Shaul

doi:10.1073/pnas.2010275117

The glutathione peroxidase 8 (GPX8)/IL-6/STAT3 axis is essential in maintaining an aggressive breast cancer phenotype

Anees Khatib, Balakrishnan Solaimuthu, Michal Ben Yosef, Areej Abu Rmaileh, Mayur Tanna, Gidi Oren, Michal Schlesinger Frisch, Jonathan H. Axelrod, Michal Lichtenstein, Yoav D. Shaul^*

^*Corresponding author for this work

Department of Biochemistry and Molecular Biology

Research output: Contribution to journal › Article › peer-review

39 Scopus citations

Abstract

One of the emerging hallmarks of cancer illustrates the importance of metabolic reprogramming, necessary to synthesize the building blocks required to fulfill the high demands of rapidly proliferating cells. However, the proliferation-independent instructive role of metabolic enzymes in tumor plasticity is still unclear. Here, we provide evidence that glutathione peroxidase 8 (GPX8), a poorly characterized enzyme that resides in the endoplasmic reticulum, is an essential regulator of tumor aggressiveness. We found that GPX8 expression was induced by the epithelial-mesenchymal transition (EMT) program. Moreover, in breast cancer patients, GPX8 expression significantly correlated with known mesenchymal markers and poor prognosis. Strikingly, GPX8 knockout in mesenchymal-like cells (MDA-MB-231) resulted in an epithelial-like morphology, downregulation of EMT characteristics, and loss of cancer stemness features. In addition, GPX8 knockout significantly delayed tumor initiation and decreased its growth rate in mice. We found that these GPX8 loss-dependent phenotypes were accompanied by the repression of crucial autocrine factors, in particular, interleukin-6 (IL-6). In these cells, IL-6 bound to the soluble receptor (sIL6R), stimulating the JAK/STAT3 signaling pathway by IL-6 trans-signaling mechanisms, so promoting cancer aggressiveness. We observed that in GPX8 knockout cells, this signaling mechanism was impaired as sIL6R failed to activate the JAK/STAT3 signaling pathway. Altogether, we present the GPX8/IL-6/STAT3 axis as a metabolic-inflammatory pathway that acts as a robust regulator of cancer cell aggressiveness.

Original language	English
Pages (from-to)	21420-21431
Number of pages	12
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	117
Issue number	35
DOIs	https://doi.org/10.1073/pnas.2010275117
State	Published - 1 Sep 2020

Bibliographical note

Funding Information:
We thank the members of the Y.D.S. laboratory. This work was supported by the Israel Science Foundation (Grant 1816/16), the Israel Cancer Association (Grant 20180062, Abraham Rutstein funds), and the Hebrew University start-up funds. B.S. is supported by the Lady Davis Fellowship for postdoctoral researchers at The Hebrew University of Jerusalem. The Genomic Applications Laboratory of the Core Research Facility, The Faculty of Medicine, The Hebrew University of Jerusalem, Israel, performed the RNA-Seq data analysis. Prof. Rotem Karni, Hebrew University, designed the primers for IL6R alternative splice isoform analysis. Prof. Irit Sagi, Weizmann Institute of Science, assisted the ADAM17 activity assay.

Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.

Keywords

Cancer metabolism
Epithelial-mesenchymal transition
GPX8
JAK/STAT3 signaling

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1073/pnas.2010275117

Cite this

Khatib, A., Solaimuthu, B., Yosef, M. B., Rmaileh, A. A., Tanna, M., Oren, G., Frisch, M. S., Axelrod, J. H., Lichtenstein, M., & Shaul, Y. D. (2020). The glutathione peroxidase 8 (GPX8)/IL-6/STAT3 axis is essential in maintaining an aggressive breast cancer phenotype. Proceedings of the National Academy of Sciences of the United States of America, 117(35), 21420-21431. https://doi.org/10.1073/pnas.2010275117

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abstract = "One of the emerging hallmarks of cancer illustrates the importance of metabolic reprogramming, necessary to synthesize the building blocks required to fulfill the high demands of rapidly proliferating cells. However, the proliferation-independent instructive role of metabolic enzymes in tumor plasticity is still unclear. Here, we provide evidence that glutathione peroxidase 8 (GPX8), a poorly characterized enzyme that resides in the endoplasmic reticulum, is an essential regulator of tumor aggressiveness. We found that GPX8 expression was induced by the epithelial-mesenchymal transition (EMT) program. Moreover, in breast cancer patients, GPX8 expression significantly correlated with known mesenchymal markers and poor prognosis. Strikingly, GPX8 knockout in mesenchymal-like cells (MDA-MB-231) resulted in an epithelial-like morphology, downregulation of EMT characteristics, and loss of cancer stemness features. In addition, GPX8 knockout significantly delayed tumor initiation and decreased its growth rate in mice. We found that these GPX8 loss-dependent phenotypes were accompanied by the repression of crucial autocrine factors, in particular, interleukin-6 (IL-6). In these cells, IL-6 bound to the soluble receptor (sIL6R), stimulating the JAK/STAT3 signaling pathway by IL-6 trans-signaling mechanisms, so promoting cancer aggressiveness. We observed that in GPX8 knockout cells, this signaling mechanism was impaired as sIL6R failed to activate the JAK/STAT3 signaling pathway. Altogether, we present the GPX8/IL-6/STAT3 axis as a metabolic-inflammatory pathway that acts as a robust regulator of cancer cell aggressiveness.",

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Khatib, A, Solaimuthu, B, Yosef, MB, Rmaileh, AA, Tanna, M, Oren, G, Frisch, MS, Axelrod, JH, Lichtenstein, M & Shaul, YD 2020, 'The glutathione peroxidase 8 (GPX8)/IL-6/STAT3 axis is essential in maintaining an aggressive breast cancer phenotype', Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 35, pp. 21420-21431. https://doi.org/10.1073/pnas.2010275117

The glutathione peroxidase 8 (GPX8)/IL-6/STAT3 axis is essential in maintaining an aggressive breast cancer phenotype. / Khatib, Anees; Solaimuthu, Balakrishnan; Yosef, Michal Ben et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 117, No. 35, 01.09.2020, p. 21420-21431.

Research output: Contribution to journal › Article › peer-review

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AU - Solaimuthu, Balakrishnan

AU - Yosef, Michal Ben

AU - Rmaileh, Areej Abu

AU - Tanna, Mayur

AU - Oren, Gidi

AU - Frisch, Michal Schlesinger

AU - Axelrod, Jonathan H.

AU - Lichtenstein, Michal

AU - Shaul, Yoav D.

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The glutathione peroxidase 8 (GPX8)/IL-6/STAT3 axis is essential in maintaining an aggressive breast cancer phenotype

Abstract

Bibliographical note

Keywords

UN SDGs

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