DJ-1 suppresses ferroptosis through preserving the activity of S-adenosyl homocysteine hydrolase.

Abstract	Ferroptosis is a newly characterized form of regulated cell death mediated by iron-dependent accumulation of lipid reactive oxygen species and holds great potential for cancer therapy. However, the molecular mechanisms underlying ferroptosis remain largely elusive. In this study, we define an integrative role of DJ-1 in ferroptosis. Inhibition of DJ-1 potently enhances the sensitivity of tumor cells to ferroptosis inducers both in vitro and in vivo. Metabolic analysis and metabolite rescue assay reveal that DJ-1 depletion inhibits the transsulfuration pathway by disrupting the formation of the S-adenosyl homocysteine hydrolase tetramer and impairing its activity. Consequently, more ferroptosis is induced when homocysteine generation is decreased, which might be the only source of glutathione biosynthesis when cystine uptake is blocked. Thus, our findings show that DJ-1 determines the response of cancer cells to ferroptosis, and highlight a candidate therapeutic target to potentially improve the effect of ferroptosis-based antitumor therapy.
Authors	Ji Cao, Xiaobing Chen, Li Jiang, Bin Lu, Meng Yuan, Difeng Zhu, Hong Zhu, Qiaojun He, Bo Yang, Meidan Ying
Journal	Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 1251 (03 06 2020) ISSN: 2041-1723 [Electronic] England
PMID	32144268 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents Intracellular Signaling Peptides and Proteins Piperazines RNA, Small Interfering adenosylhomocysteine hydrolase-like protein 1, mouse erastin Homocysteine PARK7 protein, human PARK7 protein, mouse Protein Deglycase DJ-1 AHCY protein, human Adenosylhomocysteinase Glutathione
Topics	Adenosylhomocysteinase (metabolism) Animals Antineoplastic Agents (pharmacology, therapeutic use) Cell Line, Tumor Female Ferroptosis (drug effects, physiology) Fibroblasts Glutathione (biosynthesis) HEK293 Cells Homocysteine (metabolism) Humans Intracellular Signaling Peptides and Proteins (metabolism) Mice Mice, Knockout Neoplasms (drug therapy, pathology) Piperazines (pharmacology) Primary Cell Culture Protein Deglycase DJ-1 (genetics, metabolism) Protein Multimerization RNA, Small Interfering (metabolism) Xenograft Model Antitumor Assays

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!