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<p>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 Zn<sup>2+</sup> finger transcription factor ZNF281 increases synthesis and release of inosine and hypoxanthine, which bind the A<sub>2A</sub> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月25日

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  • 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,
  • Gopinath Sutendra

摘要

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.