Polyamine-mediated ferroptosis amplification acts as a targetable vulnerability in cancer

Guoshu Bi, Jiaqi Liang, Yunyi Bian, Guangyao Shan, Yiwei Huang, Tao Lu, Huan Zhang, Xing Jin, Zhencong Chen, Mengnan Zhao, Hong Fan, Qun Wang, Boyi Gan () and Cheng Zhan ()
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Guoshu Bi: Fudan University
Jiaqi Liang: Fudan University
Yunyi Bian: Fudan University
Guangyao Shan: Fudan University
Yiwei Huang: Fudan University
Tao Lu: Fudan University
Huan Zhang: Fudan University
Xing Jin: Fudan University
Zhencong Chen: Fudan University
Mengnan Zhao: Fudan University
Hong Fan: Fudan University
Qun Wang: Fudan University
Boyi Gan: The University of Texas MD Anderson Cancer Center
Cheng Zhan: Fudan University

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Targeting ferroptosis, an iron-dependent form of regulated cell death triggered by the lethal overload of lipid peroxides, in cancer therapy is impeded by our limited understanding of the intersection of tumour’s metabolic feature and ferroptosis vulnerability. In the present study, arginine is identified as a ferroptotic promoter using a metabolites library. This effect is mainly achieved through arginine’s conversion to polyamines, which exerts their potent ferroptosis-promoting property in an H2O2-dependent manner. Notably, the expression of ornithine decarboxylase 1 (ODC1), the critical enzyme catalysing polyamine synthesis, is significantly activated by the ferroptosis signal——iron overload——through WNT/MYC signalling, as well as the subsequent elevated polyamine synthesis, thus forming a ferroptosis-iron overload-WNT/MYC-ODC1-polyamine-H2O2 positive feedback loop that amplifies ferroptosis. Meanwhile, we notice that ferroptotic cells release enhanced polyamine-containing extracellular vesicles into the microenvironment, thereby further sensitizing neighbouring cells to ferroptosis and accelerating the “spread” of ferroptosis in the tumour region. Besides, polyamine supplementation also sensitizes cancer cells or xenograft tumours to radiotherapy or chemotherapy through inducing ferroptosis. Considering that cancer cells are often characterized by elevated intracellular polyamine pools, our results indicate that polyamine metabolism exposes a targetable vulnerability to ferroptosis and represents an exciting opportunity for therapeutic strategies for cancer.

Date: 2024
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DOI: 10.1038/s41467-024-46776-w

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