Tumour initiated purinergic signalling promotes cardiomyocyte RBFOX1 degradation and cardiotoxicity from DNA damaging anticancer agents

Saymon Tejay, Maria Areli Lorenzana-Carrillo, Guocheng Huang, Seyed Amirhossein Tabatabaei Dakhili, Yuan -Yuan Zhao, Farah Eaton, Michelle Mendiola Pla, Dawn E. Bowles, Adam Kinnaird, D. Ian Paterson, Edith Pituskin, John R. Ussher, Evangelos D. Michelakis and Gopinath Sutendra ()
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Saymon Tejay: Department of Medicine, University of Alberta
Maria Areli Lorenzana-Carrillo: Department of Medicine, University of Alberta
Guocheng Huang: Cancer Research Institute of Northern Alberta, University of Alberta
Seyed Amirhossein Tabatabaei Dakhili: Cardiovascular Research Institute, University of Alberta
Yuan -Yuan Zhao: Department of Medicine, University of Alberta
Farah Eaton: Cardiovascular Research Institute, University of Alberta
Michelle Mendiola Pla: Department of Surgery, Duke University
Dawn E. Bowles: Department of Surgery, Duke University
Adam Kinnaird: Cancer Research Institute of Northern Alberta, University of Alberta
D. Ian Paterson: University of Ottawa Heart Institute, University of Ottawa
Edith Pituskin: Cancer Research Institute of Northern Alberta, University of Alberta
John R. Ussher: Cardiovascular Research Institute, University of Alberta
Evangelos D. Michelakis: Department of Medicine, University of Alberta
Gopinath Sutendra: Department of Medicine, University of Alberta

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract It is well established tumour cells secrete signalling factors affecting distant normal tissues. What remains unresolved is whether these factors initiate a signalling cascade rendering terminally differentiated cardiomyocytes susceptible to apoptosis, a feature of chemotherapy-induced cardiotoxicity (CIC). Here we show in MANTICORE trial cancer patients, cumulative baseline plasma levels of the nucleoside inosine and its derivative hypoxanthine predict cardiotoxicity. We found the Zn2+ finger transcription factor ZNF281 increases synthesis and release of inosine and hypoxanthine, which bind the A2A receptor on cardiomyocytes, activating CAMKIIδ which phosphorylates the postnatal mRNA splicing factor RBFOX1, resulting in its caspase-dependent degradation. RBFOX1 loss reverts cardiomyocytes to a less mature state with open chromatin and susceptibility to DNA damage, apoptosis or CIC, when treated with DNA intercalating or alkylating anticancer agents. These findings suggest cumulative inosine and hypoxanthine levels may be a biomarker predicting patient susceptibility to DNA damaging anti-cancer agents.

Date: 2025
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DOI: 10.1038/s41467-025-62172-4

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