Metabolic disorders sensitise endometrial carcinoma through endoplasmic reticulum stress
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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-12-01
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| Series: | Cellular & Molecular Biology Letters |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s11658-022-00412-x |
| _version_ | 1798004928156794880 |
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| author | Jingyi Zhou Yanying Lin Xiao Yang Boqiang Shen Juan Hao Jiaqi Wang Jianliu Wang |
| author_facet | Jingyi Zhou Yanying Lin Xiao Yang Boqiang Shen Juan Hao Jiaqi Wang Jianliu Wang |
| author_sort | Jingyi Zhou |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T12:31:11Z |
| format | Article |
| id | doaj.art-650e5450de41400f8fa111983179bf09 |
| institution | Directory Open Access Journal |
| issn | 1425-8153 1689-1392 |
| language | English |
| last_indexed | 2024-04-11T12:31:11Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Cellular & Molecular Biology Letters |
| spelling | doaj.art-650e5450de41400f8fa111983179bf092022-12-22T04:23:44ZengBMCCellular & Molecular Biology Letters1425-81531689-13922022-12-0127112010.1186/s11658-022-00412-xMetabolic disorders sensitise endometrial carcinoma through endoplasmic reticulum stressJingyi Zhou0Yanying Lin1Xiao Yang2Boqiang Shen3Juan Hao4Jiaqi Wang5Jianliu Wang6Department of Obstetrics and Gynecology, Peking University People’s HospitalDepartment of Obstetrics and Gynecology, Peking University People’s HospitalDepartment of Obstetrics and Gynecology, Peking University People’s HospitalDepartment of Obstetrics and Gynecology, Peking University People’s HospitalDepartment of Obstetrics and Gynecology, Peking University People’s HospitalDepartment of Obstetrics and Gynecology, Peking University People’s HospitalDepartment of Obstetrics and Gynecology, Peking University People’s HospitalAbstract 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.https://doi.org/10.1186/s11658-022-00412-xEndometrial carcinomaMetabolic disordersInsulinEndoplasmic reticulum stressSaturated fatty acid |
| spellingShingle | Jingyi Zhou Yanying Lin Xiao Yang Boqiang Shen Juan Hao Jiaqi Wang Jianliu Wang Metabolic disorders sensitise endometrial carcinoma through endoplasmic reticulum stress Cellular & Molecular Biology Letters Endometrial carcinoma Metabolic disorders Insulin Endoplasmic reticulum stress Saturated fatty acid |
| title | Metabolic disorders sensitise endometrial carcinoma through endoplasmic reticulum stress |
| title_full | Metabolic disorders sensitise endometrial carcinoma through endoplasmic reticulum stress |
| title_fullStr | Metabolic disorders sensitise endometrial carcinoma through endoplasmic reticulum stress |
| title_full_unstemmed | Metabolic disorders sensitise endometrial carcinoma through endoplasmic reticulum stress |
| title_short | Metabolic disorders sensitise endometrial carcinoma through endoplasmic reticulum stress |
| title_sort | metabolic disorders sensitise endometrial carcinoma through endoplasmic reticulum stress |
| topic | Endometrial carcinoma Metabolic disorders Insulin Endoplasmic reticulum stress Saturated fatty acid |
| url | https://doi.org/10.1186/s11658-022-00412-x |
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