Cysteamine dioxygenase (ADO) governs cancer cell mitochondrial redox homeostasis through proline metabolism
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 <i>ADO</i> 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.
Authors
- Anna Dvorkin‐Gheva (ORCID: https://orcid.org/0000-0001-7295-7440)
- Lucie Malbeteau
- Stephen W. Chung (ORCID: https://orcid.org/0000-0001-7986-2903)
- Shahbaz Khan (ORCID: https://orcid.org/0000-0001-9352-0088)
- Julie A. Reisz (ORCID: https://orcid.org/0000-0002-7296-4963)
- Sandy Che-Eun S. Lee (ORCID: https://orcid.org/0000-0002-7691-8104)
- Helia Mohammadi (ORCID: https://orcid.org/0009-0001-9112-5559)
- Marianne Koritzinsky (ORCID: https://orcid.org/0000-0003-0547-2480)
- Rob A. Cairns (ORCID: https://orcid.org/0000-0001-9540-7927)
- Bradly G. Wouters (ORCID: https://orcid.org/0000-0002-8187-592X)
- M. Teresa Ciudad (ORCID: https://orcid.org/0000-0002-2007-4619)
- Thomas Kislinger (ORCID: https://orcid.org/0000-0003-3525-5540)
- Rachel Culp‐Hill (ORCID: https://orcid.org/0000-0003-3000-083X)
- Courtney L. Jones (ORCID: https://orcid.org/0000-0003-0672-1493)
- Angelo D’Alessandro (ORCID: https://orcid.org/0000-0002-2258-6490)
- Tracy L. McGaha (ORCID: https://orcid.org/0000-0003-4721-9301)
- Andrea Hye An Pyo (ORCID: https://orcid.org/0009-0000-8286-052X)
- Vincent Rondeau (ORCID: https://orcid.org/0000-0002-9513-5703)
- Ji Zhang (ORCID: https://orcid.org/0009-0005-8912-373X)
Institutions
- University Health Network (CA)
- University of Toronto (CA)
- Princess Margaret Cancer Centre (CA)
- University of Colorado Anschutz Medical Campus (US)
Publication Details
- Journal
- Science Advances
- Published
- 2024-10-02
- DOI
- https://doi.org/10.1126/sciadv.adq0355
- Citations
- 12
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 2.81
Funders
- Princess Margaret Cancer Foundation