The metabolic role of the CD73/adenosine signaling pathway in HTR-8/SVneo cells: A Double-Edged Sword?
Guangmin Song,
Dan Zhang,
Jianan Zhu,
Andi Wang,
Xiaobo Zhou,
Ting-Li Han,
Hua Zhang
Affiliations
Guangmin Song
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Rd, Yuzhong District, Chongqing, 400016, China; Canada-China-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, 1 Yixueyuan Rd, Yuzhong District, Chongqing, 400016, China; The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, 1 Youyi Rd, Yuzhong District, Chongqing, 400016, China
Dan Zhang
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Rd, Yuzhong District, Chongqing, 400016, China; Canada-China-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, 1 Yixueyuan Rd, Yuzhong District, Chongqing, 400016, China; The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, 1 Youyi Rd, Yuzhong District, Chongqing, 400016, China
Jianan Zhu
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Rd, Yuzhong District, Chongqing, 400016, China; Canada-China-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, 1 Yixueyuan Rd, Yuzhong District, Chongqing, 400016, China; The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, 1 Youyi Rd, Yuzhong District, Chongqing, 400016, China
Andi Wang
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Rd, Yuzhong District, Chongqing, 400016, China
Xiaobo Zhou
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Rd, Yuzhong District, Chongqing, 400016, China; Canada-China-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, 1 Yixueyuan Rd, Yuzhong District, Chongqing, 400016, China
Ting-Li Han
Department of Obstetrics and Gynaecology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Rd, Chongqing, 400010, China; Corresponding author.
Hua Zhang
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Rd, Yuzhong District, Chongqing, 400016, China; Canada-China-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, 1 Yixueyuan Rd, Yuzhong District, Chongqing, 400016, China; Corresponding author. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Rd, Yuzhong District, Chongqing 400016, China.
The ecto-5′-nucleotidase (CD73)/adenosine signaling pathway has been reported to regulate tumor epithelial-mesenchymal transition (EMT), migration and proliferation. However, little is known about the metabolic mechanisms underlying its role in trophoblast proliferation and migration. In this study, we aimed to investigate the metabolic role of the CD73/adenosine signaling pathway on the proliferation and migration of trophoblast. We found that CD73 levels were upregulated in preeclamptic placentas compared with the placentas of normotensive pregnant women. EMT and migration of HTR-8/SVneo cells were enhanced when treated with a CD73 inhibitor (100 μM) in vitro. Conversely, excessive adenosine (25 or 50 μM) suppressed trophoblast cell EMT, migration and proliferation. RNA-seq, metabolomics and seahorse findings showed that adenosine treatment resulted in increased expression of PDK1, suppression of aerobic respiration, glycolysis and amino acids synthesis, as well as increased utilization of short-chain fatty acids (SCFAs). Furthermore, the 13C-adenosine isotope tracking experiment demonstrated that adenosine served as a carbon source for the tricarboxylic acid (TCA) cycle. Our results reveal the role of adenosine in regulating trophoblast energy metabolism is like a double-edged sword - either inhibiting aerobic respiration or supplementing carbon sources into metabolic flux. CD73/adenosine signaling regulated trophoblast EMT, migration, and proliferation by modulating energy metabolism. This study indicates that CD73/adenosine signaling potentially plays a role in the occurrence of placenta-derived diseases, including preeclampsia.
