FBW7-NRA41-SCD1 axis synchronously regulates apoptosis and ferroptosis in pancreatic cancer cells

Zeng Ye; Qifeng Zhuo; Qiangsheng Hu; Xiaowu Xu; Mengqi Liu; Zheng Zhang; Wenyan Xu; Wensheng Liu; Guixiong Fan; Yi Qin; Xianjun Yu; Shunrong Ji

doi:10.1016/j.redox.2020.101807

FBW7-NRA41-SCD1 axis synchronously regulates apoptosis and ferroptosis in pancreatic cancer cells

Redox Biol. 2021 Jan:38:101807. doi: 10.1016/j.redox.2020.101807. Epub 2020 Nov 24.

Authors

Zeng Ye¹, Qifeng Zhuo¹, Qiangsheng Hu¹, Xiaowu Xu¹, Mengqi Liu¹, Zheng Zhang¹, Wenyan Xu¹, Wensheng Liu¹, Guixiong Fan¹, Yi Qin², Xianjun Yu³, Shunrong Ji⁴

Affiliations

¹ 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.
² 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. Electronic address: yuxianjun@fudanpci.org.
³ 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. Electronic address: qinyi@fudanpci.org.
⁴ 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. Electronic address: jishunrong@fudanpci.org.

Abstract

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.

Keywords: Apoptosis; FBW7; Ferroptosis; Pancreatic cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
Cell Line, Tumor
F-Box-WD Repeat-Containing Protein 7
Ferroptosis*
Humans
Pancreatic Neoplasms* / drug therapy
Pancreatic Neoplasms* / genetics
Stearoyl-CoA Desaturase

Substances

F-Box-WD Repeat-Containing Protein 7
FBXW7 protein, human
SCD1 protein, human
Stearoyl-CoA Desaturase