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

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

666 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
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 - 15 Aug 2017
Externally published	Yes

Keywords

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

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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.",

keywords = "ACSL4, NOX, NRF2, SLC7A11, TP53, ddp4, ferroptosis, iron, lipid peroxidation, precision medicine",

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

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s)",

year = "2017",

month = aug,

day = "15",

doi = "10.1016/j.celrep.2017.07.055",

language = "English",

volume = "20",

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journal = "Cell Reports",

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T1 - The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity

AU - Xie, Yangchun

AU - Zhu, Shan

AU - Song, Xinxin

AU - Sun, Xiaofang

AU - Fan, Yong

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

PY - 2017/8/15

Y1 - 2017/8/15

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.

KW - ACSL4

KW - NOX

KW - NRF2

KW - SLC7A11

KW - TP53

KW - ddp4

KW - ferroptosis

KW - iron

KW - lipid peroxidation

KW - precision medicine

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DO - 10.1016/j.celrep.2017.07.055

M3 - Article

C2 - 28813679

AN - SCOPUS:85027880924

SN - 2211-1247

VL - 20

SP - 1692

EP - 1704

JO - Cell Reports

JF - Cell Reports

IS - 7

ER -

The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity

Abstract

Keywords

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