The glutathione peroxidase 8 (GPX8)/IL-6/STAT3 axis is essential in maintaining an aggressive breast cancer phenotype.
Anees KhatibBalakrishnan SolaimuthuMichal Ben YosefAreej Abu RmailehMayur TannaGidi OrenMichal Schlesinger FrischJonathan H AxelrodMichal LichtensteinYoav David ShaulPublished in: Proceedings of the National Academy of Sciences of the United States of America (2020)
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.
Keyphrases
- epithelial mesenchymal transition
- poor prognosis
- signaling pathway
- induced apoptosis
- cell cycle arrest
- papillary thyroid
- pi k akt
- long non coding rna
- stem cells
- transforming growth factor
- oxidative stress
- bone marrow
- squamous cell
- endoplasmic reticulum stress
- cell proliferation
- cell death
- hydrogen peroxide
- binding protein
- transcription factor
- squamous cell carcinoma
- lymph node metastasis