Eunkyung Leea,1, Ahyoung Choia,b, 1, Yukyung Juna,b, Namhee Kimc, Jong In Yookc, Soo Youl Kimd, Sanghyuk Leea,b,*, Sang Won Kanga,*
a Department of Life Science and Ewha Womans University, Seoul, 03760, South Korea
b Bio-Information Science, Ewha Womans University, Seoul, 03760, South Korea
c Department of Oral Pathology, School of Dentistry, Yonsei University, Seoul, 03722, South Korea
d Division of Basic Science, Research Institute, National Cancer Institute, Goyang, 10408, South Korea
*Corresponding author : Sanghyuk Lee, Sang Won Kang
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.
Glutathione peroxidase; Triple-negative breast cancer; Metastasis; Adhesion; Focal adhesion kinase