机构：[1]State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & West China Hospital of Stomatology, Sichuan University, Chengdu, China,[2]Department of Cleft Lip and Palate Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China,[3]Women’s Health Research Institute, Department of Obstetrics and Gynecology, University of Tu¨bingen, Tu¨bingen, Germany,[4]Department of Obstetrics and Gynecology, Juntendo University School of Medicine, Tokyo, Japan,[5]Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, China,[6]Institute for Medical Genetics and Applied Genomics, University of Tu¨bingen, Tu¨bingen, Germany,[7]Department of Internal Medicine III, University of Tu¨bingen, Tu¨bingen, Germany
LEFTY2 (endometrial bleeding associated factor; EBAF or LEFTYA), a cytokine released shortly before menstrual bleeding, is a negative regulator of cell proliferation and tumour growth. LEFTY2 down-regulates Na+/H+ exchanger activity with subsequent inhibition of glycolytic flux and lactate production in endometrial cancer cells. Glucose can be utilized not only for glycolysis but also for glycogen formation. Both glycolysis and glycogen formation require cellular glucose uptake which could be accomplished by the Na+ coupled glucose transporter-1 (SGLT1; SLC5A1). The present study therefore explored whether LEFTY2 modifies endometrial SGLT1 expression and activity as well as glycogen formation. Ishikawa and HEC1a cells were exposed to LEFTY2, SGLT1 and glycogen synthase (GYS1) transcript levels determined by qRT-PCR. SGLT1, GYS1 and phospho-GYS1 protein abundance was quantified by western blotting, cellular glucose uptake from 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG) uptake, and cellular glycogen content utilizing an enzymatic assay and subsequent colorimetry. As a result, a 48-hour treatment with LEFTY2 significantly increased SGLT1 and GYS1 transcript levels as well as SGLT1 and GYS1 protein abundance in both Ishikawa and HEC1a cells. 2-NBDG uptake and cellular glycogen content were upregulated significantly in Ishikawa (type 1) but not in type 2 endometrial HEC1a cells, although there was a tendency of increased 2-NBDG uptake. Further, none of the effects were seen in human benign endometrial cells (HESCs). Interestingly, in both Ishikawa and HEC1a cells, a co-treatment with TGF-β reduced SGLT1, GYS and phospho-GYS protein levels, and thus reduced glycogen levels and again HEC1a cells had no significant change. In conclusion, LEFTY2 up-regulates expression and activity of the Na+ coupled glucose transporter SGLT1 and glycogen synthase GYS1 in a cell line specific manner. We further show the treatment with LEFTY2 fosters cellular glucose uptake and glycogen formation and TGF-β can negate this effect in endometrial cancer cells.
基金：
This work was supported by funding to
M.S.S the Zukunftskonzept award (Deutsche
Forschungsgemeinschaft; ZUK63), the IZKF (2510-
0-0) and the Margarete von Wrangell-
Habilitationsprogramm fu¨r Frauen (31-7635.41/
118/3; Ministerium fu¨r Wissenschaft, Forschung und Kunst Baden-Wu¨rttemberg). We acknowledge
support by Deutsche Forschungsgemeinschaft and
Open Access Publishing Fund of the University of
Tu¨bingen. The funders had no role in study design,
data collection and analysis, decision to publish, or
preparation of the manuscript.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2020]版：
大类|3 区综合性期刊
小类|3 区综合性期刊
最新[2023]版：
大类|3 区综合性期刊
小类|3 区综合性期刊
第一作者：
第一作者机构：[1]State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & West China Hospital of Stomatology, Sichuan University, Chengdu, China,[2]Department of Cleft Lip and Palate Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China,[3]Women’s Health Research Institute, Department of Obstetrics and Gynecology, University of Tu¨bingen, Tu¨bingen, Germany,
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Zeng Ni,Okumura Toshiyuki,Alauddin Md,et al.LEFTY2/endometrial bleeding-associated factor up-regulates Na+ Coupled Glucose Transporter SGLT1 expression and Glycogen Accumulation in Endometrial Cancer Cells.[J].PloS one.2020,15(4):e0230044.doi:10.1371/journal.pone.0230044.
APA：
Zeng Ni,Okumura Toshiyuki,Alauddin Md,Khozooei Shayan,Rajaxavier Janet...&Salker Madhuri S.(2020).LEFTY2/endometrial bleeding-associated factor up-regulates Na+ Coupled Glucose Transporter SGLT1 expression and Glycogen Accumulation in Endometrial Cancer Cells..PloS one,15,(4)
MLA：
Zeng Ni,et al."LEFTY2/endometrial bleeding-associated factor up-regulates Na+ Coupled Glucose Transporter SGLT1 expression and Glycogen Accumulation in Endometrial Cancer Cells.".PloS one 15..4(2020):e0230044
