The PI3K/Akt/GSK-3β/ROS/eIF2B pathway promotes breast cancer growth and metastasis via suppression of NK cell cytotoxicity and tumor cell susceptibility

• Published in: Cancer biology & medicine Vol. 16; no. 1; pp. 38 - 54
• Main Authors: Jin, Fengjiao, Wu, Zhaozhen, Hu, Xiao, Zhang, Jiahui, Gao, Zihe, Han, Xiao, Qin, Junfang, Li, Chen, Wang, Yue
• Format: Journal Article
• Language: English
• Published: China State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China 01.02.2019; School of Medicine, Nankai University, Tianjin 300071, China%Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China%School of Medicine, Nankai University, Tianjin 300071, China; Chinese Anti-Cancer Association; China Anti-Cancer Association
• Subjects: breast cancer; eIF2B; GSK-3β; NK cells; NKG2D/NKG2DLs; Original; ROS; GSK-3β; breast cancer; NK cells; NKG2D/NKG2DLs; eIF2B; ROS
• ISSN: 2095-3941; 2095-3941
• DOI: 10.20892/j.issn.2095-3941.2018.0253

To examine the effect of pSer9-GSK-3β on breast cancer and to determine whether the underlying metabolic and immunological mechanism is associated with ROS/eIF2B and natural killer (NK) cells. We employed TWS119 to inactivate GSK-3β by phosphorylating Ser9 and explored its effect on breast cancer and NK cells. The expression of GSK-3β, natural killer group 2 member D (NKG2D) ligands, eIF2B was quantified by PCR and Western blot. We measured intracellular reactive oxygen species (ROS) and mitochondrial ROS using DCFH-DA and MitoSOX probe, respectively, and conducted quantitative analysis of cellular respiration on 4T1 cells with mitochondrial respiratory chain complex I/III kits. Our investigation revealed that TWS119 downregulated NKG2D ligands (H60a and Rae1), suppressed the cytotoxicity of NK cells, and promoted the migration of 4T1 murine breast cancer cells. Nevertheless, LY290042, which attenuates p-GSK-3β formation by inhibiting the PI3K/Akt pathway, reversed these effects. We also found that higher expression of pSer9-GSK-3β induced higher levels of ROS, and observed that abnormality of mitochondrial respiratory chain complex I/III function induced the dysfunction of GSK-3β-induced electron transport chain, naturally disturbing the ROS level. In addition, the expression of NOX3 and NOX4 was significantly up-regulated, which affected the generation of ROS and associated with the metastasis of breast cancer. Furthermore, we found that the expression of pSer535-eIF2B promoted the expression of NKG2D ligands (Mult-1 and Rae1) following by expression of pSer9-GSK-3β and generation of ROS. The PI3K/Akt/GSK-3β/ROS/eIF2B pathway could regulate NK cell activity and sensitivity of tumor cells to NK cells, which resulted in breast cancer growth and lung metastasis. Thus, GSK-3β is a promising target of anti-tumor therapy.