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 3rd; Rui Kang; Guido Kroemer; Daolin Tang

doi:10.1016/j.celrep.2017.07.055

The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity

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

Authors

Yangchun Xie¹, Shan Zhu², Xinxin Song³, Xiaofang Sun², Yong Fan², Jinbao Liu², Meizuo Zhong⁴, Hua Yuan⁵, Lin Zhang⁶, Timothy R Billiar³, Michael T Lotze³, Herbert J Zeh 3rd³, Rui Kang³, Guido Kroemer⁷, Daolin Tang⁸

Affiliations

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.

PMID: 28813679
DOI: 10.1016/j.celrep.2017.07.055

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.

MeSH terms

Adamantane / analogs & derivatives
Adamantane / pharmacology
Animals
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Apoptosis / genetics
Caco-2 Cells
Cell Line, Tumor
Cell Membrane / drug effects*
Cell Membrane / metabolism
Cell Membrane / pathology
Cell Nucleus / drug effects
Cell Nucleus / metabolism
Colorectal Neoplasms / drug therapy*
Colorectal Neoplasms / enzymology
Colorectal Neoplasms / genetics
Colorectal Neoplasms / pathology
Dipeptidyl Peptidase 4 / genetics*
Dipeptidyl Peptidase 4 / metabolism
Dipeptidyl-Peptidase IV Inhibitors / pharmacology
Gene Expression Regulation, Neoplastic*
HCT116 Cells
Humans
Injections, Subcutaneous
Iron / metabolism
Lipid Peroxidation
Mice
Mice, Nude
Nitriles / pharmacology
Piperazines / pharmacology*
Pyrrolidines / pharmacology
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Signal Transduction
Tumor Suppressor Protein p53 / antagonists & inhibitors
Tumor Suppressor Protein p53 / deficiency
Tumor Suppressor Protein p53 / genetics*
Vildagliptin
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Dipeptidyl-Peptidase IV Inhibitors
Nitriles
Piperazines
Pyrrolidines
RNA, Small Interfering
Tumor Suppressor Protein p53
erastin
Iron
DPP4 protein, human
Dipeptidyl Peptidase 4
Vildagliptin
Adamantane

Abstract

MeSH terms

Substances

Grants and funding