Activation of ALOX12 by a multi-organelle-orienting photosensitizer drives ACSL4-independent cell ferroptosis
Abstract Ferroptosis is a recently-defined tumor suppression mechanism, but the sensitivity of many tumorigenic cells to ferroptosis is limited by their deficient expression of acyl-CoA synthetase long-chain family member 4 (ACSL4). Here, we report the discovery of a photosensitizer, namely TPCI, wh...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-12-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05462-9 |
| _version_ | 1798005114551664640 |
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| author | Xiuxia Wang Yuanhong Chen Xiang Yang Lianghui Cheng Zhenyan He Yanru Xin Shan Huang Fanling Meng Peijing Zhang Liang Luo |
| author_facet | Xiuxia Wang Yuanhong Chen Xiang Yang Lianghui Cheng Zhenyan He Yanru Xin Shan Huang Fanling Meng Peijing Zhang Liang Luo |
| author_sort | Xiuxia Wang |
| collection | DOAJ |
| description | Abstract Ferroptosis is a recently-defined tumor suppression mechanism, but the sensitivity of many tumorigenic cells to ferroptosis is limited by their deficient expression of acyl-CoA synthetase long-chain family member 4 (ACSL4). Here, we report the discovery of a photosensitizer, namely TPCI, which can evoke ACSL4-independent ferroptosis of cancer cells in photodynamic therapy. Through co-localization with 12-lipoxygenase (ALOX12) in multiple subcellular organelles, TPCI activates ALOX12 to generate lipid reactive oxygen species in large quantity and trigger cell ferroptosis. Intriguingly, confining TPCI exclusively in lysosomes switches the cell death from ferroptosis to apoptosis. More strikingly, the ferroptosis mediated by TPCI-induced ALOX12 activation does not require the participation of ACSL4. Therefore, our study identifies TPCI as the first ALOX12 activator to induce ferroptosis independent of ACSL4, which renders a viable therapeutic approach on the basis of distinct ferroptosis of cancer cells, regardless their ACSL4 expressions. |
| first_indexed | 2024-04-11T12:35:09Z |
| format | Article |
| id | doaj.art-0c6fd77914c24ba6aea002202cadbef5 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-11T12:35:09Z |
| publishDate | 2022-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-0c6fd77914c24ba6aea002202cadbef52022-12-22T04:23:39ZengNature Publishing GroupCell Death and Disease2041-48892022-12-01131211110.1038/s41419-022-05462-9Activation of ALOX12 by a multi-organelle-orienting photosensitizer drives ACSL4-independent cell ferroptosisXiuxia Wang0Yuanhong Chen1Xiang Yang2Lianghui Cheng3Zhenyan He4Yanru Xin5Shan Huang6Fanling Meng7Peijing Zhang8Liang Luo9Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityNational Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and TechnologyNational Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and TechnologyNational Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and TechnologyNational Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and TechnologyNational Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and TechnologyNational Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and TechnologyNational Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and TechnologyNational Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and TechnologyNational Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and TechnologyAbstract Ferroptosis is a recently-defined tumor suppression mechanism, but the sensitivity of many tumorigenic cells to ferroptosis is limited by their deficient expression of acyl-CoA synthetase long-chain family member 4 (ACSL4). Here, we report the discovery of a photosensitizer, namely TPCI, which can evoke ACSL4-independent ferroptosis of cancer cells in photodynamic therapy. Through co-localization with 12-lipoxygenase (ALOX12) in multiple subcellular organelles, TPCI activates ALOX12 to generate lipid reactive oxygen species in large quantity and trigger cell ferroptosis. Intriguingly, confining TPCI exclusively in lysosomes switches the cell death from ferroptosis to apoptosis. More strikingly, the ferroptosis mediated by TPCI-induced ALOX12 activation does not require the participation of ACSL4. Therefore, our study identifies TPCI as the first ALOX12 activator to induce ferroptosis independent of ACSL4, which renders a viable therapeutic approach on the basis of distinct ferroptosis of cancer cells, regardless their ACSL4 expressions.https://doi.org/10.1038/s41419-022-05462-9 |
| spellingShingle | Xiuxia Wang Yuanhong Chen Xiang Yang Lianghui Cheng Zhenyan He Yanru Xin Shan Huang Fanling Meng Peijing Zhang Liang Luo Activation of ALOX12 by a multi-organelle-orienting photosensitizer drives ACSL4-independent cell ferroptosis Cell Death and Disease |
| title | Activation of ALOX12 by a multi-organelle-orienting photosensitizer drives ACSL4-independent cell ferroptosis |
| title_full | Activation of ALOX12 by a multi-organelle-orienting photosensitizer drives ACSL4-independent cell ferroptosis |
| title_fullStr | Activation of ALOX12 by a multi-organelle-orienting photosensitizer drives ACSL4-independent cell ferroptosis |
| title_full_unstemmed | Activation of ALOX12 by a multi-organelle-orienting photosensitizer drives ACSL4-independent cell ferroptosis |
| title_short | Activation of ALOX12 by a multi-organelle-orienting photosensitizer drives ACSL4-independent cell ferroptosis |
| title_sort | activation of alox12 by a multi organelle orienting photosensitizer drives acsl4 independent cell ferroptosis |
| url | https://doi.org/10.1038/s41419-022-05462-9 |
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