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

Research output: Contribution to journalArticle

110 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 languageEnglish (US)
Pages (from-to)1692-1704
Number of pages13
JournalCell Reports
Volume20
Issue number7
DOIs
StatePublished - Aug 15 2017
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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