RRC ID 82490
Author Lee SCS, Pyo AHA, Mohammadi H, Zhang J, Dvorkin-Gheva A, Malbeteau L, Chung S, Khan S, Ciudad MT, Rondeau V, Cairns RA, Kislinger T, McGaha TL, Wouters BG, Reisz JA, Culp-Hill R, D'Alessandro A, Jones CL, Koritzinsky M.
Title Cysteamine dioxygenase (ADO) governs cancer cell mitochondrial redox homeostasis through proline metabolism.
Journal Sci Adv
Abstract 2-Aminoethanethiol dioxygenase (ADO) is a thiol dioxygenase that sulfinylates cysteamine and amino-terminal cysteines in polypeptides. The pathophysiological roles of ADO remain largely unknown. Here, we demonstrate that ADO expression represents a vulnerability in cancer cells, as ADO depletion led to loss of proliferative capacity and survival in cancer cells and reduced xenograft growth. In contrast, generation of the ADO knockout mouse revealed high tolerance for ADO depletion in adult tissues. To understand the mechanism underlying ADO's essentiality in cancer cells, we characterized the cell proteome and metabolome following depletion of ADO. This revealed that ADO depletion leads to toxic levels of polyamines which can be driven by ADO's substrate cysteamine. Polyamine accumulation in turn stimulated expression of proline dehydrogenase (PRODH) which resulted in mitochondrial hyperactivity and ROS production, culminating in cell toxicity. This work identifies ADO as a unique vulnerability in cancer cells, due to its essential role in maintenance of redox homeostasis through restraining polyamine levels and proline catabolism.
Volume 10(40)
Pages eadq0355
Published 2024-10-4
DOI 10.1126/sciadv.adq0355
PMID 39356760
PMC PMC11446280
MeSH Animals Cell Line, Tumor Cell Proliferation Cysteamine / metabolism Dioxygenases / metabolism Homeostasis* Humans Mice Mice, Knockout Mitochondria* / metabolism Neoplasms / genetics Neoplasms / metabolism Neoplasms / pathology Oxidation-Reduction* Polyamines / metabolism Proline* / metabolism Proline Oxidase / genetics Proline Oxidase / metabolism Reactive Oxygen Species / metabolism
Resource
Human and Animal Cells HuH-6(RCB1367)