Calpain 2 regulates IL-1α secretion and inhibits tumor development via modulating calpain 1 expression in the tumor microenvironment
Tumor-promoting inflammation significantly impacts cancer progression, and targeting inflammatory cytokines has emerged as a promising therapeutic approach in clinical trials. Interleukin (IL)-1α, a member of the IL-1 cytokine family, plays a crucial role in both inflammation and carcinogenesis. How...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2025-12-01
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| Series: | OncoImmunology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2025.2451444 |
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| author | Zuhairah Binte Hanafi Yu Mei Huey Yee Teo Ying Zhu Chew Chin Yong Lionel Jing Wen Chiu Jinhua Lu Haiyan Liu |
| author_facet | Zuhairah Binte Hanafi Yu Mei Huey Yee Teo Ying Zhu Chew Chin Yong Lionel Jing Wen Chiu Jinhua Lu Haiyan Liu |
| author_sort | Zuhairah Binte Hanafi |
| collection | DOAJ |
| description | Tumor-promoting inflammation significantly impacts cancer progression, and targeting inflammatory cytokines has emerged as a promising therapeutic approach in clinical trials. Interleukin (IL)-1α, a member of the IL-1 cytokine family, plays a crucial role in both inflammation and carcinogenesis. How IL-1α is secreted in the tumor microenvironment has been poorly understood, and we previously showed that calpain 1 cleaves pro-IL-1α for mature IL-1α secretion, which exacerbates hepatocellular carcinoma by recruiting myeloid-derived suppressor cells. In this study, we report that calpain 2 also modulates IL-1α secretion. Notably, a deficiency in calpain 2 resulted in enhanced hepatocellular carcinoma development within an IL-1α-enriched tumor microenvironment. Further investigations revealed that calpain 2 deficiency increased calpain 1 expression, implying a compensatory mechanism between the two calpains. Mechanistically, calpain 2 deficiency led to increased expression of FoxO3, which is a forkhead transcription factor that promotes calpain 1 expression. Collectively, these results suggest that calpain 2 modulates calpain 1 expression, and therefore IL-1α secretion through the induction of FoxO3, offering novel potential therapeutic targets for cancer treatment. |
| format | Article |
| id | doaj-art-6657dfa0b5274491aa77a92a9ae229b8 |
| institution | Kabale University |
| issn | 2162-402X |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj-art-6657dfa0b5274491aa77a92a9ae229b82025-01-13T12:56:55ZengTaylor & Francis GroupOncoImmunology2162-402X2025-12-0114110.1080/2162402X.2025.2451444Calpain 2 regulates IL-1α secretion and inhibits tumor development via modulating calpain 1 expression in the tumor microenvironmentZuhairah Binte Hanafi0Yu Mei1Huey Yee Teo2Ying Zhu3Chew Chin Yong Lionel4Jing Wen Chiu5Jinhua Lu6Haiyan Liu7Immunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, SingaporeImmunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, SingaporeImmunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, SingaporeImmunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, SingaporeImmunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, SingaporeImmunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, SingaporeImmunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, SingaporeImmunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, SingaporeTumor-promoting inflammation significantly impacts cancer progression, and targeting inflammatory cytokines has emerged as a promising therapeutic approach in clinical trials. Interleukin (IL)-1α, a member of the IL-1 cytokine family, plays a crucial role in both inflammation and carcinogenesis. How IL-1α is secreted in the tumor microenvironment has been poorly understood, and we previously showed that calpain 1 cleaves pro-IL-1α for mature IL-1α secretion, which exacerbates hepatocellular carcinoma by recruiting myeloid-derived suppressor cells. In this study, we report that calpain 2 also modulates IL-1α secretion. Notably, a deficiency in calpain 2 resulted in enhanced hepatocellular carcinoma development within an IL-1α-enriched tumor microenvironment. Further investigations revealed that calpain 2 deficiency increased calpain 1 expression, implying a compensatory mechanism between the two calpains. Mechanistically, calpain 2 deficiency led to increased expression of FoxO3, which is a forkhead transcription factor that promotes calpain 1 expression. Collectively, these results suggest that calpain 2 modulates calpain 1 expression, and therefore IL-1α secretion through the induction of FoxO3, offering novel potential therapeutic targets for cancer treatment.https://www.tandfonline.com/doi/10.1080/2162402X.2025.2451444Calpain 2hepatocellular carcinomaIL-1αMDSCstumor microenvironment |
| spellingShingle | Zuhairah Binte Hanafi Yu Mei Huey Yee Teo Ying Zhu Chew Chin Yong Lionel Jing Wen Chiu Jinhua Lu Haiyan Liu Calpain 2 regulates IL-1α secretion and inhibits tumor development via modulating calpain 1 expression in the tumor microenvironment OncoImmunology Calpain 2 hepatocellular carcinoma IL-1α MDSCs tumor microenvironment |
| title | Calpain 2 regulates IL-1α secretion and inhibits tumor development via modulating calpain 1 expression in the tumor microenvironment |
| title_full | Calpain 2 regulates IL-1α secretion and inhibits tumor development via modulating calpain 1 expression in the tumor microenvironment |
| title_fullStr | Calpain 2 regulates IL-1α secretion and inhibits tumor development via modulating calpain 1 expression in the tumor microenvironment |
| title_full_unstemmed | Calpain 2 regulates IL-1α secretion and inhibits tumor development via modulating calpain 1 expression in the tumor microenvironment |
| title_short | Calpain 2 regulates IL-1α secretion and inhibits tumor development via modulating calpain 1 expression in the tumor microenvironment |
| title_sort | calpain 2 regulates il 1α secretion and inhibits tumor development via modulating calpain 1 expression in the tumor microenvironment |
| topic | Calpain 2 hepatocellular carcinoma IL-1α MDSCs tumor microenvironment |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2025.2451444 |
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