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

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, 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.

Glutathione Peroxidase 8 Suppression by Histone Deacetylase Inhibitors Enhances Endoplasmic Reticulum Stress and Cell Death by Oxidative Stress in Hepatocellular Carcinoma Cells

“…Similar to our results, HDAC inhibitors reduced the expression of GPX8 protein in fibroblasts derived from a Niemann-Pick type C patient [29] and Gpx8 mRNA in SK-MEL-3 melanoma cells [30]. From these results, we speculated that downregulation of GPX8 may cause an increase in hydrogen peroxide and oxidative stress levels in the ER, which interrupts proper folding and maturation of secreted and membrane proteins by inducing aberrant disulfide bonds, as reported previously [31]. It is well established that HDACi hyperacetylates histones, which results in transcriptionally active euchromatin.…”

The molecular feature of macrophages in tumor immune microenvironment of glioma patients

“…M2 macrophage-secreted CHI3L1 could promote gastric and breast cancer metastasis [42] , and CHI3L1 modulates an immune suppressive microenvironment by reprogramming M2-like TAM in GBM [43] . TNFAIP6, RBP1, FBXO17, and GPX8 promote metastasis and invasiveness of tumor [44] , [45] , [46] , [47] . SLC43A3 and ADAM12 have been revealed as the biomarker and therapeutic target in tumor patients [48] , [49] .…”

Regulatory effect of the MAFG‑AS1/miR‑150‑5p/MYB axis on the proliferation and migration of breast cancer cells

“…Breast cancer is a major health threat to women worldwide ( 1 , 2 ). Although a number of studies have investigated the cellular and molecular mechanisms underlying the occurrence and development of breast cancer ( 31 - 33 ), early detection is hindered by the lack of effective diagnostic biomarkers. Numerous studies have indicated that lncRNAs may be used as potential therapeutic targets or prognostic markers of breast cancer ( 34 ).…”