The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity

Yangchun Xie; Shan Zhu; Xinxin Song; Xiaofang Sun; Yong Fan; Jinbao Liu; Meizuo Zhong; Hua Yuan; Lin Zhang; Timothy R. Billiar; Michael T. Lotze; Herbert J. Zeh; Rui Kang; Guido Kroemer; Daolin Tang

doi:10.1016/j.celrep.2017.07.055

The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity

Yangchun Xie, Shan Zhu, Xinxin Song, Xiaofang Sun, Yong Fan, Jinbao Liu, Meizuo Zhong, Hua Yuan, Lin Zhang, Timothy R. Billiar, Michael T. Lotze, Herbert J. Zeh, Rui Kang, Guido Kroemer^*, Daolin Tang

^*Corresponding author for this work

Obstetrics and Gynecology

Research output: Contribution to journal › Article › peer-review

651 Scopus citations

Abstract

Ferroptosis is a form of regulated cell death that may facilitate the selective elimination of tumor cells. The tumor suppressor p53 (TP53) has been demonstrated to promote ferroptosis via a transcription-dependent mechanism. Here, we show that TP53 limits erastin-induced ferroptosis by blocking dipeptidyl-peptidase-4 (DPP4) activity in a transcription-independent manner. Loss of TP53 prevents nuclear accumulation of DPP4 and thus facilitates plasma-membrane-associated DPP4-dependent lipid peroxidation, which finally results in ferroptosis. These findings reveal a direct molecular link between TP53 and DPP4 in the control of lipid metabolism and may provide a precision medicine strategy for the treatment of colorectal cancer by induction of ferroptosis.

Original language	English (US)
Pages (from-to)	1692-1704
Number of pages	13
Journal	Cell Reports
Volume	20
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2017.07.055
State	Published - Aug 15 2017

Funding

We thank Christine Heiner (Department of Surgery, University of Pittsburgh) for her critical reading of the manuscript. This work was supported by grants from the US NIH ( R01GM115366 , R01CA160417 , and R01CA181450 ), the Natural Science Foundation of Guangdong Province ( 2016A030308011 ), the American Cancer Society (research scholar grant RSG-16-014-01-CDD ), the National Natural Science Foundation of China ( 31671435 , 81400132 , and 8177100253 ), the National Funds of Developing Local Colleges and Universities Grant ( B16056001 ), a Frontier and Key Technology Innovation Special Grant from the Department of Science and Technology of Guangdong Province ( 2016B030229008 ), and the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2017). This project partly utilized University of Pittsburgh Cancer Institute shared resources supported by award P30CA047904 . G.K. is supported by the Ligue contre le Cancer (équipe labelisée); Agence National de la Recherche (ANR) Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases ; Association pour la recherche sur le cancer (ARC) ; Cancéropôle Ile-de-France ; Institut National du Cancer (INCa) ; Institut Universitaire de France ; Fondation pour la Recherche Médicale (FRM) ; the European Commission (ArtForce) ; the European Research Council (ERC) ; the LeDucq Foundation ; the LabEx Immuno-Oncology ; the RHU Torino Lumière ; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE) ; the SIRIC Cancer Research and Personalized Medicine (CARPEM) ; and the Paris Alliance of Cancer Research Institutes (PACRI) .

Keywords

ACSL4
ddp4
ferroptosis
iron
lipid peroxidation
NOX
NRF2
precision medicine
SLC7A11
TP53

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2017.07.055

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title = "The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity",

abstract = "Ferroptosis is a form of regulated cell death that may facilitate the selective elimination of tumor cells. The tumor suppressor p53 (TP53) has been demonstrated to promote ferroptosis via a transcription-dependent mechanism. Here, we show that TP53 limits erastin-induced ferroptosis by blocking dipeptidyl-peptidase-4 (DPP4) activity in a transcription-independent manner. Loss of TP53 prevents nuclear accumulation of DPP4 and thus facilitates plasma-membrane-associated DPP4-dependent lipid peroxidation, which finally results in ferroptosis. These findings reveal a direct molecular link between TP53 and DPP4 in the control of lipid metabolism and may provide a precision medicine strategy for the treatment of colorectal cancer by induction of ferroptosis.",

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AU - Liu, Jinbao

AU - Zhong, Meizuo

AU - Yuan, Hua

AU - Zhang, Lin

AU - Billiar, Timothy R.

AU - Lotze, Michael T.

AU - Zeh, Herbert J.

AU - Kang, Rui

AU - Kroemer, Guido

AU - Tang, Daolin

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N2 - Ferroptosis is a form of regulated cell death that may facilitate the selective elimination of tumor cells. The tumor suppressor p53 (TP53) has been demonstrated to promote ferroptosis via a transcription-dependent mechanism. Here, we show that TP53 limits erastin-induced ferroptosis by blocking dipeptidyl-peptidase-4 (DPP4) activity in a transcription-independent manner. Loss of TP53 prevents nuclear accumulation of DPP4 and thus facilitates plasma-membrane-associated DPP4-dependent lipid peroxidation, which finally results in ferroptosis. These findings reveal a direct molecular link between TP53 and DPP4 in the control of lipid metabolism and may provide a precision medicine strategy for the treatment of colorectal cancer by induction of ferroptosis.

AB - Ferroptosis is a form of regulated cell death that may facilitate the selective elimination of tumor cells. The tumor suppressor p53 (TP53) has been demonstrated to promote ferroptosis via a transcription-dependent mechanism. Here, we show that TP53 limits erastin-induced ferroptosis by blocking dipeptidyl-peptidase-4 (DPP4) activity in a transcription-independent manner. Loss of TP53 prevents nuclear accumulation of DPP4 and thus facilitates plasma-membrane-associated DPP4-dependent lipid peroxidation, which finally results in ferroptosis. These findings reveal a direct molecular link between TP53 and DPP4 in the control of lipid metabolism and may provide a precision medicine strategy for the treatment of colorectal cancer by induction of ferroptosis.

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The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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