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Cell Rep. 2017 Aug 15;20(7):1692-1704. doi: 10.1016/j.celrep.2017.07.055.

The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity.

Author information

1
The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Protein Modification and Degradation Laboratory, Guangzhou Medical University, Guangzhou, Guangdong 510510, China; Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
2
The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Protein Modification and Degradation Laboratory, Guangzhou Medical University, Guangzhou, Guangdong 510510, China.
3
Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
4
Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
5
School of Nursing, Jilin University, Changchun, Jilin 130021, China.
6
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
7
Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, 75006 Paris, France; Institut National de la Santé et de la Recherche Médicale, U1138, Paris, France; Université Pierre et Marie Curie, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, 94800 Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France; Department of Women's and Children's Health, Karolinska University Hospital, 17176 Stockholm, Sweden. Electronic address: kroemer@orange.fr.
8
The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Protein Modification and Degradation Laboratory, Guangzhou Medical University, Guangzhou, Guangdong 510510, China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: tangd2@upmc.edu.

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

PMID:
28813679
DOI:
10.1016/j.celrep.2017.07.055
[Indexed for MEDLINE]
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