2. Academic Validation
  3. Metabolic disorders sensitise endometrial carcinoma through endoplasmic reticulum stress

Metabolic disorders sensitise endometrial carcinoma through endoplasmic reticulum stress

  • Cell Mol Biol Lett. 2022 Dec 16;27(1):110. doi: 10.1186/s11658-022-00412-x.
Jingyi Zhou # 1,  Yanying Lin # 1 2 3,  Xiao Yang 1,  Boqiang Shen 1,  Juan Hao 1,  Jiaqi Wang 1,  Jianliu Wang 4 5
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, 100044, China.
  • 2 Center of Reproductive Medicine, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, China.
  • 3 Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital, Fuzhou, China.
  • 4 Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, 100044, China. wangjianliu@pkuph.edu.cn.
  • 5 Beijing Key Laboratory of Female Pelvic Floor Disorders Disease, Beijing, 100044, China. wangjianliu@pkuph.edu.cn.
  • # Contributed equally.
PMID: 36526973 DOI: 10.1186/s11658-022-00412-x
Abstract

Background: Metabolic disorder is considered a well-established risk factor for endometrial carcinoma (EC). However, the mechanism remains unclear. Insulin resistance and excessive flux of free fatty acids serve as fundamental pathogenic factors in metabolic disorders, including obesity and type 2 diabetes. The aim of this study was to test the correlation between Insulin resistance and dyslipidaemia in EC and to determine the effect of Insulin and saturated fatty acids on EC cells.

Methods: A retrospective study on the medical records of patients with EC and RNA-seq from the TCGA database analysed with edgR and Gene Ontology (GO) were used to assess the correlation of dyslipidaemia and diabetes as well as obesity. Crystal violet assays and CCK-8 assays were used to detect the proliferation of EC cells, and Annexin V-PI was used to examine Apoptosis. Transient changes in mitochondrial CA2+ and Reactive Oxygen Species (ROS) were monitored via confocal microscopy. DNA damage was assessed by comet assays. Changes in signalling pathways were detected via phospho-kinase array. western blotting was used to assess the molecular changes in endoplasmic reticulum (ER) stress and DNA damage.

Results: We found that glucose metabolism disorders accompanied dyslipidaemia in patients with EC. As a key regulator of glucose metabolism disorders, Insulin promoted DNA damage, ROS and CA2+ homoeostasis imbalance in a panel of established EC cell lines. Interestingly, excessive Insulin boosted saturated fatty acid-induced pro-apoptotic effects in EC cells. Furthermore, our data showed that Insulin synergised with saturated fatty acids to activate the mechanistic target of rapamycin kinase/70 kDa ribosomal protein S6 kinase (mTOR/p70S6K) pathway and ER stress, resulting in CA2+ release from ER and unfolded protein response (UPR) activation, which contributed to combined Insulin and saturated fatty acid treatment-induced Apoptosis and tumour progression.

Conclusions: Our data are the first to illustrate that impaired glucose metabolism accelerates dyslipidaemia-promoted EC progression, which is attributed to hyperinsulinaemia and saturated fatty acid-induced CA2+ dyshomoeostasis and UPR activation in EC cells via ER stress.

Keywords

Endometrial carcinoma; Endoplasmic reticulum stress; Insulin; Metabolic disorders; Saturated fatty acid.

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