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

Author(s): Zeng Ye ^a ^, ^b ^, ^c ^, ^d ^, ¹ , Qifeng Zhuo ^a ^, ^b ^, ^c ^, ^d , Qiangsheng Hu ^a ^, ^b ^, ^c ^, ^d ^, ¹ , Xiaowu Xu ^a ^, ^b ^, ^c ^, ^d ^, ¹ , Mengqi liu ^a ^, ^b ^, ^c ^, ^d , Zheng Zhang ^a ^, ^b ^, ^c ^, ^d , Wenyan Xu ^a ^, ^b ^, ^c ^, ^d , Wensheng Liu ^a ^, ^b ^, ^c ^, ^d , Guixiong Fan ^a ^, ^b ^, ^c ^, ^d , Yi Qin ^a ^, ^b ^, ^c ^, ^d ^, ^∗∗ , Xianjun Yu ^a ^, ^b ^, ^c ^, ^d ^, ^∗∗∗ , Shunrong Ji ^a ^, ^b ^, ^c ^, ^d ^, ^∗

Publication date (Electronic): 24 November 2020

Journal: Redox Biology

Publisher: Elsevier

Keywords: Pancreatic cancer, FBW7, Apoptosis, Ferroptosis

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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.

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Highlights

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Ferroptosis possesses great potential in pancreatic cancer therapy.
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FBW7 synchronously induces apoptosis and ferroptosis.
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Activation of apoptosis and ferroptosis potentiates cytotoxic effect of gemcitabine.

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Most cited references 42

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Cancer statistics, 2019

Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2019)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data, available through 2015, were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data, available through 2016, were collected by the National Center for Health Statistics. In 2019, 1,762,450 new cancer cases and 606,880 cancer deaths are projected to occur in the United States. Over the past decade of data, the cancer incidence rate (2006-2015) was stable in women and declined by approximately 2% per year in men, whereas the cancer death rate (2007-2016) declined annually by 1.4% and 1.8%, respectively. The overall cancer death rate dropped continuously from 1991 to 2016 by a total of 27%, translating into approximately 2,629,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the racial gap in cancer mortality is slowly narrowing, socioeconomic inequalities are widening, with the most notable gaps for the most preventable cancers. For example, compared with the most affluent counties, mortality rates in the poorest counties were 2-fold higher for cervical cancer and 40% higher for male lung and liver cancers during 2012-2016. Some states are home to both the wealthiest and the poorest counties, suggesting the opportunity for more equitable dissemination of effective cancer prevention, early detection, and treatment strategies. A broader application of existing cancer control knowledge with an emphasis on disadvantaged groups would undoubtedly accelerate progress against cancer.

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Ferroptosis: an iron-dependent form of nonapoptotic cell death.

Scott J. Dixon, Kathryn Lemberg, Michael Lamprecht … (2012)

Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.

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Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

Suzy Torti, Donna D. Zhang, K.A. Woerpel … (2019)

Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.

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Author and article information

Contributors

Yi Qin

Xianjun Yu

Shunrong Ji

Journal

Journal ID (nlm-ta): Redox Biol

Journal ID (iso-abbrev): Redox Biol

Title: Redox Biology

Publisher: Elsevier

ISSN (Electronic): 2213-2317

Publication date PMC-release: 24 November 2020

Publication date Collection: January 2021

Publication date (Electronic): 24 November 2020

Volume: 38

Electronic Location Identifier: 101807

Affiliations

[a ]Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China

[b ]Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

[c ]Shanghai Pancreatic Cancer Institute, Shanghai, China

[d ]Pancreatic Cancer Institute, Fudan University, Shanghai, China

Author notes

[∗ ]Corresponding author. Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, Shanghai, 200032, China. jishunrong@ 123456fudanpci.org

[∗∗ ]Corresponding author. Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, Shanghai, 200032, China. yuxianjun@ 123456fudanpci.org

[∗∗∗ ]Corresponding author. Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, Shanghai, 200032, China. qinyi@ 123456fudanpci.org

[1]

Z. Ye, Q. Zhuo, and Q. Hu contributed equally to this article.

Article

Publisher Item ID: S2213-2317(20)31012-0 Publisher ID: 101807

DOI: 10.1016/j.redox.2020.101807

PMC ID: 7710650

PubMed ID: 33271455

SO-VID: 20776716-4fe5-4553-9546-d4fdde0db1a0

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 1 July 2020

Date revision received : 7 November 2020

Date accepted : 18 November 2020

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

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Abstract

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Karger: Oncology

Most cited references 42

Cancer statistics, 2019

Ferroptosis: an iron-dependent form of nonapoptotic cell death.

Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

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