FBW7-NRA41-SCD1 axis synchronously regulates apoptosis and ferroptosis in pancreatic cancer cells
FBW7 functions as a tumor suppressor by targeting oncoproteins for degradation. Our previous study found FBW7 was low expressed in pancreatic cancer due to sustained activation of Ras-Raf-MEK-ERK pathway, which destabilized FBW7 by phosphorylating at Thr205. MicroPET/CT imaging results revealed that...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231720310120 |
| _version_ | 1819276117914157056 |
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| author | Zeng Ye Qifeng Zhuo Qiangsheng Hu Xiaowu Xu Mengqi liu Zheng Zhang Wenyan Xu Wensheng Liu Guixiong Fan Yi Qin Xianjun Yu Shunrong Ji |
| author_facet | Zeng Ye Qifeng Zhuo Qiangsheng Hu Xiaowu Xu Mengqi liu Zheng Zhang Wenyan Xu Wensheng Liu Guixiong Fan Yi Qin Xianjun Yu Shunrong Ji |
| author_sort | Zeng Ye |
| collection | DOAJ |
| description | FBW7 functions as a tumor suppressor by targeting oncoproteins for degradation. Our previous study found FBW7 was low expressed in pancreatic cancer due to sustained activation of Ras-Raf-MEK-ERK pathway, which destabilized FBW7 by phosphorylating at Thr205. MicroPET/CT imaging results revealed that FBW7 substantially decreased 18F-fluorodeoxyglucose uptake in xenograft tumors. Mechanistically, FBW7 inhibited glucose metabolism via c-Myc/TXNIP axis. But in these studies, we observed FBW7 down-regulated genes were widely involved in redox reaction and lipid metabolism. Here we reanalyzed previous gene expression profiling and conducted targeted cell metabolites analysis. Results revealed that FBW7 regulated lipid peroxidation and promoted ferroptosis, a non-apoptotic form of cell death. Mechanistically, we found FBW7 inhibited the expression of stearoyl-CoA desaturase (SCD1) via inhibiting nuclear receptor subfamily 4 group A member 1 (NR4A1). SCD1 was reported to inhibit both ferroptosis and apoptosis, which was consistent with the function of FBW7 and NR4A1, another FBW7 down-regulated gene in the gene expression profiling. Moreover, FBW7 potentiated cytotoxic effect of gemcitabine via activating ferroptosis and apoptosis. Combination ferroptosis inducers and apoptosis activators could also significantly potentiated cytotoxic effect of gemcitabine in pancreatic cancer. Therefore, our findings might provide new strategies for the comprehensive treatment of pancreatic cancer. |
| first_indexed | 2024-12-23T23:35:08Z |
| format | Article |
| id | doaj.art-192d3a14aeb64caba20289ed20dcb403 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-23T23:35:08Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-192d3a14aeb64caba20289ed20dcb4032022-12-21T17:25:54ZengElsevierRedox Biology2213-23172021-01-0138101807FBW7-NRA41-SCD1 axis synchronously regulates apoptosis and ferroptosis in pancreatic cancer cellsZeng Ye0Qifeng Zhuo1Qiangsheng Hu2Xiaowu Xu3 Mengqi liu4Zheng Zhang5Wenyan Xu6Wensheng Liu7Guixiong Fan8Yi Qin9Xianjun Yu10Shunrong Ji11Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, ChinaDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, ChinaDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, ChinaDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, ChinaDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, ChinaDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, ChinaDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, ChinaDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, ChinaDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, ChinaDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China; Corresponding author. Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, Shanghai, 200032, China.Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China; Corresponding author. Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, Shanghai, 200032, China.Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China; Corresponding author. Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, Shanghai, 200032, China.FBW7 functions as a tumor suppressor by targeting oncoproteins for degradation. Our previous study found FBW7 was low expressed in pancreatic cancer due to sustained activation of Ras-Raf-MEK-ERK pathway, which destabilized FBW7 by phosphorylating at Thr205. MicroPET/CT imaging results revealed that FBW7 substantially decreased 18F-fluorodeoxyglucose uptake in xenograft tumors. Mechanistically, FBW7 inhibited glucose metabolism via c-Myc/TXNIP axis. But in these studies, we observed FBW7 down-regulated genes were widely involved in redox reaction and lipid metabolism. Here we reanalyzed previous gene expression profiling and conducted targeted cell metabolites analysis. Results revealed that FBW7 regulated lipid peroxidation and promoted ferroptosis, a non-apoptotic form of cell death. Mechanistically, we found FBW7 inhibited the expression of stearoyl-CoA desaturase (SCD1) via inhibiting nuclear receptor subfamily 4 group A member 1 (NR4A1). SCD1 was reported to inhibit both ferroptosis and apoptosis, which was consistent with the function of FBW7 and NR4A1, another FBW7 down-regulated gene in the gene expression profiling. Moreover, FBW7 potentiated cytotoxic effect of gemcitabine via activating ferroptosis and apoptosis. Combination ferroptosis inducers and apoptosis activators could also significantly potentiated cytotoxic effect of gemcitabine in pancreatic cancer. Therefore, our findings might provide new strategies for the comprehensive treatment of pancreatic cancer.http://www.sciencedirect.com/science/article/pii/S2213231720310120Pancreatic cancerFBW7ApoptosisFerroptosis |
| spellingShingle | Zeng Ye Qifeng Zhuo Qiangsheng Hu Xiaowu Xu Mengqi liu Zheng Zhang Wenyan Xu Wensheng Liu Guixiong Fan Yi Qin Xianjun Yu Shunrong Ji FBW7-NRA41-SCD1 axis synchronously regulates apoptosis and ferroptosis in pancreatic cancer cells Redox Biology Pancreatic cancer FBW7 Apoptosis Ferroptosis |
| title | FBW7-NRA41-SCD1 axis synchronously regulates apoptosis and ferroptosis in pancreatic cancer cells |
| title_full | FBW7-NRA41-SCD1 axis synchronously regulates apoptosis and ferroptosis in pancreatic cancer cells |
| title_fullStr | FBW7-NRA41-SCD1 axis synchronously regulates apoptosis and ferroptosis in pancreatic cancer cells |
| title_full_unstemmed | FBW7-NRA41-SCD1 axis synchronously regulates apoptosis and ferroptosis in pancreatic cancer cells |
| title_short | FBW7-NRA41-SCD1 axis synchronously regulates apoptosis and ferroptosis in pancreatic cancer cells |
| title_sort | fbw7 nra41 scd1 axis synchronously regulates apoptosis and ferroptosis in pancreatic cancer cells |
| topic | Pancreatic cancer FBW7 Apoptosis Ferroptosis |
| url | http://www.sciencedirect.com/science/article/pii/S2213231720310120 |
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