Aldo-keto Reductase 1B10 (AKR1B10) Suppresses Sensitivity of Ferroptosis in TNBC by Activating the AKT/GSK3β/Nrf2/GPX4 Axis
Background: Aldo-keto reductase 1B10 (AKR1B10) is expressed in various malignant tissues. Several studies have highlighted the essential function of AKR1B10 in lipid metabolism and in the detoxification of lipid peroxides. The aim of this research was to explore the role of AKR1B1...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
IMR Press
2025-06-01
|
| Series: | Frontiers in Bioscience-Landmark |
| Subjects: | |
| Online Access: | https://www.imrpress.com/journal/FBL/30/6/10.31083/FBL36615 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1839636692139507712 |
|---|---|
| author | Shanli Wu Gun Yang Xiaosha Wen Yi Lin Shenglong Wang Jing Wang Quan Liu Dixian Luo |
| author_facet | Shanli Wu Gun Yang Xiaosha Wen Yi Lin Shenglong Wang Jing Wang Quan Liu Dixian Luo |
| author_sort | Shanli Wu |
| collection | DOAJ |
| description | Background: Aldo-keto reductase 1B10 (AKR1B10) is expressed in various malignant tissues. Several studies have highlighted the essential function of AKR1B10 in lipid metabolism and in the detoxification of lipid peroxides. The aim of this research was to explore the role of AKR1B10 in the susceptibility of MDA-MB-231 cells to ferroptosis. These cells serve as a model for triple-negative breast cancer (TNBC). Methods: Lentiviral transfection was used to establish stable cell lines with high or low expression of AKR1B10. Our model of ferroptosis used the ferroptosis activator RSL3, and the specific ferroptosis inhibitor ferrostatin-1 (Fer-1) to rescue cell death. Stable cell lines were treated with the specific inhibitor OSU-T315 directed against phosphorylation of Ser473 in protein kinase B (AKT) and Ser9 in glycogen synthase kinase 3 beta (GSK3β), either alone or in combination with RSL3. A fatty acid stress model was established using palmitic acid (PA) or arachidonic acid (AA), either in the presence or absence of serum starvation and with or without co-treatment with RSL3. Cell viability was evaluated with the cell counting kit-8 (CCK8) assay and lipid peroxidation levels by flow cytometry after staining with C11 BODIPY 581/591. Exploration of the underlying mechanisms was conducted through RNA sequencing and bioinformatics analysis. Western blotting was performed to evaluate protein levels, and quantitative real-time polymerase chain reaction (qPCR) was used to evaluate transcript levels. Results: Western blot and qPCR analyses validated the successful establishment of stable MDA-MB-231 cell lines with and without AKR1B10 overexpression. Cell viability and lipid reactive oxygen species (ROS) assays showed that AKR1B10 suppressed ferroptosis in the RSL3-induced cell death model. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) analyses indicated the phosphatidylinositol 3-kinase (PI3K)-AKT pathway was likely to play a role in the underlying mechanisms. AKR1B10 increased the expression of glutathione peroxidase 4 (GPX4), thus potentially implicating the AKT/GSK3β/nuclear factor erythroid 2-related factor 2 (NRF2)/GPX4 pathway in the mechanism. These changes in protein levels were also observed by Western blot analysis after 6 h of RSL3 treatment. Under the influence of RSL3, the transcript levels of NRF2-related genes including GPX4, ferritin heavy chain 1 (FTH1), heme oxygenase 1 (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO-1) were significantly elevated in the AKR1B10 overexpression cell line, whereas that of prostaglandin-endoperoxide synthase 2 (PTGS2) was significantly reduced. Similar changes were observed after treatment with OSU-T315. AKR1B10 was found to suppress the sensitivity to ferroptosis induced by treatment with OSU-T315, PA, or AA. These phenomena were rescued by the ferroptosis inhibitor Fer-1. Conclusions: AKR1B10 appears to be an important mechanism protecting MDA-MB-231 cells from ferroptosis, possibly through the AKT Ser473/GSK3β Ser9/NRF2/GPX4 pathway. AKR1B10 may be a key factor underlying the therapeutic effect of RSL3 under different exogenous fatty acid microenvironments. |
| format | Article |
| id | doaj-art-e5b6451f53ee4b3b83d9aad03e54d3b5 |
| institution | Matheson Library |
| issn | 2768-6701 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | IMR Press |
| record_format | Article |
| series | Frontiers in Bioscience-Landmark |
| spelling | doaj-art-e5b6451f53ee4b3b83d9aad03e54d3b52025-07-07T09:22:57ZengIMR PressFrontiers in Bioscience-Landmark2768-67012025-06-013063661510.31083/FBL36615S2768-6701(25)01753-8Aldo-keto Reductase 1B10 (AKR1B10) Suppresses Sensitivity of Ferroptosis in TNBC by Activating the AKT/GSK3β/Nrf2/GPX4 AxisShanli Wu0Gun Yang1Xiaosha Wen2Yi Lin3Shenglong Wang4Jing Wang5Quan Liu6Dixian Luo7The First School of Clinical Medicine, Southern Medical University, 510000 Guangzhou, Guangdong, ChinaInstitute of Pharmacy and Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, ChinaLaboratory Medicine Centre, Shenzhen Nanshan People’s Hospital, 518052 Shenzhen, Guangdong, ChinaLaboratory Medicine Centre, Shenzhen Nanshan People’s Hospital, 518052 Shenzhen, Guangdong, ChinaFirst Clinical Medical College of Ningxia Medical University, 750000 Yinchuan, Ningxia, ChinaLaboratory Medicine Centre, Shenzhen Nanshan People’s Hospital, 518052 Shenzhen, Guangdong, ChinaMedical Laboratory Center, the Third Affiliated Hospital (The Affiliated Luohu Hospital) of Shenzhen University, 518001, Shenzhen, Guangdong, ChinaThe First School of Clinical Medicine, Southern Medical University, 510000 Guangzhou, Guangdong, ChinaBackground: Aldo-keto reductase 1B10 (AKR1B10) is expressed in various malignant tissues. Several studies have highlighted the essential function of AKR1B10 in lipid metabolism and in the detoxification of lipid peroxides. The aim of this research was to explore the role of AKR1B10 in the susceptibility of MDA-MB-231 cells to ferroptosis. These cells serve as a model for triple-negative breast cancer (TNBC). Methods: Lentiviral transfection was used to establish stable cell lines with high or low expression of AKR1B10. Our model of ferroptosis used the ferroptosis activator RSL3, and the specific ferroptosis inhibitor ferrostatin-1 (Fer-1) to rescue cell death. Stable cell lines were treated with the specific inhibitor OSU-T315 directed against phosphorylation of Ser473 in protein kinase B (AKT) and Ser9 in glycogen synthase kinase 3 beta (GSK3β), either alone or in combination with RSL3. A fatty acid stress model was established using palmitic acid (PA) or arachidonic acid (AA), either in the presence or absence of serum starvation and with or without co-treatment with RSL3. Cell viability was evaluated with the cell counting kit-8 (CCK8) assay and lipid peroxidation levels by flow cytometry after staining with C11 BODIPY 581/591. Exploration of the underlying mechanisms was conducted through RNA sequencing and bioinformatics analysis. Western blotting was performed to evaluate protein levels, and quantitative real-time polymerase chain reaction (qPCR) was used to evaluate transcript levels. Results: Western blot and qPCR analyses validated the successful establishment of stable MDA-MB-231 cell lines with and without AKR1B10 overexpression. Cell viability and lipid reactive oxygen species (ROS) assays showed that AKR1B10 suppressed ferroptosis in the RSL3-induced cell death model. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) analyses indicated the phosphatidylinositol 3-kinase (PI3K)-AKT pathway was likely to play a role in the underlying mechanisms. AKR1B10 increased the expression of glutathione peroxidase 4 (GPX4), thus potentially implicating the AKT/GSK3β/nuclear factor erythroid 2-related factor 2 (NRF2)/GPX4 pathway in the mechanism. These changes in protein levels were also observed by Western blot analysis after 6 h of RSL3 treatment. Under the influence of RSL3, the transcript levels of NRF2-related genes including GPX4, ferritin heavy chain 1 (FTH1), heme oxygenase 1 (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO-1) were significantly elevated in the AKR1B10 overexpression cell line, whereas that of prostaglandin-endoperoxide synthase 2 (PTGS2) was significantly reduced. Similar changes were observed after treatment with OSU-T315. AKR1B10 was found to suppress the sensitivity to ferroptosis induced by treatment with OSU-T315, PA, or AA. These phenomena were rescued by the ferroptosis inhibitor Fer-1. Conclusions: AKR1B10 appears to be an important mechanism protecting MDA-MB-231 cells from ferroptosis, possibly through the AKT Ser473/GSK3β Ser9/NRF2/GPX4 pathway. AKR1B10 may be a key factor underlying the therapeutic effect of RSL3 under different exogenous fatty acid microenvironments.https://www.imrpress.com/journal/FBL/30/6/10.31083/FBL36615aldo-keto reductase family 1 member b10ferroptosistriple-negative breast neoplasmsnfe2l2 |
| spellingShingle | Shanli Wu Gun Yang Xiaosha Wen Yi Lin Shenglong Wang Jing Wang Quan Liu Dixian Luo Aldo-keto Reductase 1B10 (AKR1B10) Suppresses Sensitivity of Ferroptosis in TNBC by Activating the AKT/GSK3β/Nrf2/GPX4 Axis Frontiers in Bioscience-Landmark aldo-keto reductase family 1 member b10 ferroptosis triple-negative breast neoplasms nfe2l2 |
| title | Aldo-keto Reductase 1B10 (AKR1B10) Suppresses Sensitivity of Ferroptosis in TNBC by Activating the AKT/GSK3β/Nrf2/GPX4 Axis |
| title_full | Aldo-keto Reductase 1B10 (AKR1B10) Suppresses Sensitivity of Ferroptosis in TNBC by Activating the AKT/GSK3β/Nrf2/GPX4 Axis |
| title_fullStr | Aldo-keto Reductase 1B10 (AKR1B10) Suppresses Sensitivity of Ferroptosis in TNBC by Activating the AKT/GSK3β/Nrf2/GPX4 Axis |
| title_full_unstemmed | Aldo-keto Reductase 1B10 (AKR1B10) Suppresses Sensitivity of Ferroptosis in TNBC by Activating the AKT/GSK3β/Nrf2/GPX4 Axis |
| title_short | Aldo-keto Reductase 1B10 (AKR1B10) Suppresses Sensitivity of Ferroptosis in TNBC by Activating the AKT/GSK3β/Nrf2/GPX4 Axis |
| title_sort | aldo keto reductase 1b10 akr1b10 suppresses sensitivity of ferroptosis in tnbc by activating the akt gsk3β nrf2 gpx4 axis |
| topic | aldo-keto reductase family 1 member b10 ferroptosis triple-negative breast neoplasms nfe2l2 |
| url | https://www.imrpress.com/journal/FBL/30/6/10.31083/FBL36615 |
| work_keys_str_mv | AT shanliwu aldoketoreductase1b10akr1b10suppressessensitivityofferroptosisintnbcbyactivatingtheaktgsk3bnrf2gpx4axis AT gunyang aldoketoreductase1b10akr1b10suppressessensitivityofferroptosisintnbcbyactivatingtheaktgsk3bnrf2gpx4axis AT xiaoshawen aldoketoreductase1b10akr1b10suppressessensitivityofferroptosisintnbcbyactivatingtheaktgsk3bnrf2gpx4axis AT yilin aldoketoreductase1b10akr1b10suppressessensitivityofferroptosisintnbcbyactivatingtheaktgsk3bnrf2gpx4axis AT shenglongwang aldoketoreductase1b10akr1b10suppressessensitivityofferroptosisintnbcbyactivatingtheaktgsk3bnrf2gpx4axis AT jingwang aldoketoreductase1b10akr1b10suppressessensitivityofferroptosisintnbcbyactivatingtheaktgsk3bnrf2gpx4axis AT quanliu aldoketoreductase1b10akr1b10suppressessensitivityofferroptosisintnbcbyactivatingtheaktgsk3bnrf2gpx4axis AT dixianluo aldoketoreductase1b10akr1b10suppressessensitivityofferroptosisintnbcbyactivatingtheaktgsk3bnrf2gpx4axis |