1. Polyamine-mediated ferroptosis amplification acts as a targetable vulnerability in cancer.
- Author
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Bi, Guoshu, Liang, Jiaqi, Bian, Yunyi, Shan, Guangyao, Huang, Yiwei, Lu, Tao, Zhang, Huan, Jin, Xing, Chen, Zhencong, Zhao, Mengnan, Fan, Hong, Wang, Qun, Gan, Boyi, and Zhan, Cheng
- Subjects
POLYAMINES ,ORNITHINE decarboxylase ,IRON overload ,CANCER cells ,EXTRACELLULAR vesicles ,CANCER treatment ,CELL death - 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 H
2 O2 -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-H2 O2 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. Ferroptosis plays an important role in response to radiotherapy and chemotherapy, however, the sensitivity of cancer cell to ferroptosis varies. Here, the authors show that ODC1-mediated polyamine synthesis induces ferroptosis and demonstrate the potential of targeting this axis by combining polyamine supplements with radiotherapy or chemotherapy in preclinical lung cancer models. [ABSTRACT FROM AUTHOR]- Published
- 2024
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