Triple-negative breast cancer (TNBC) cells, which do not express genes for estrogen receptor (ER), progesterone receptor (PR), and Her2/neu, develop highly aggressive and metastatic tumors resistant to chemo- and hormonal therapies. We found that expression of glutathione peroxidase-1 (Gpx1) is silenced in the non-TNBC cells but significantly maintained in the TNBC cell lines. Such Gpx1 expression plays a vital role in the metastasis of TNBC cells by regulating cell adhesion. Transcriptomic and signaling pathway analyses demonstrate that depletion of Gpx1 essentially impairs cell adhesion/spreading by down-regulating FAK/c-Src activation. Mechanistically, Gpx1 interacts with FAK kinase and prevents the kinase inactivation by H2O2, not lipid hydroperoxide. As a result, depletion of Gpx1 suppresses lung metastasis of TNBC cells in vivo. Overall, our study identifies that Gpx1 is a redox safeguard of FAK kinase and its inhibition may provide an effective way to control the metastasis of deadly malignant TNBC.
Bibliographical noteFunding Information:
We thank Prof. Eok-Soo Oh and Dr. Eun-Woo Lee for sharing antibodies and the lab members for technical assistance. This study was supported by grants from the National Research Foundation of Korea ( 2018R1A2B3006323 and 2017M3A9B6073098 ) and the National R&D Program for Cancer Control ( 1420280 ). Appendix A
© 2019 The Authors
All Science Journal Classification (ASJC) codes
- Organic Chemistry
- Clinical Biochemistry