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

Significance The cancer-dependent metabolic rewiring is mainly associated with the synthesis of building blocks that are needed to fulfill the proliferating cell metabolic requirements. However, the proliferation-independent instructive role of metabolic enzymes in tumor plasticity is still unclear. Here, we introduce glutathione peroxidase 8 (GPX8) as a metabolic enzyme that regulates cancer aggressiveness. We found that lack of GPX8 suppresses the aggressive phenotype and stemness features of the tumor cells. Mechanistically, these cells express a nonfunctional IL-6 receptor, which fails to interact with IL-6. This impaired binding hinders the activation of the downstream JAK/STAT3 signaling pathway, thereby inhibiting cancer cells transition to aggressive phenotypes. Thus, we present this GPX8/IL-6/STAT3 axis as a prototype of metabolic enzymes regulating cancer aggressiveness-associated signaling pathways. 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, down-regulation 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.