An antibiotic that mediates immune destruction of senescent cancer cells

• 成果类型: Article
• 署名作者: Raffi, Gabriele Casagrande; Chen, Jian; Feng, Xuezhao; Chen, Zhen; Lieftink, Cor; Deng, Shuang; Mo, Jinzhe; Zeng, Chuting; Steur, Marit; Wang, Jing; Bleijerveld, Onno B.; Hoekman, Liesbeth; van der Wel, Nicole; Wang, Feng; Beijersbergen, Roderick; Zheng, Jian; Bernards, Rene; Wang, Liqin
• 署名单位: Netherlands Cancer Institute; Sun Yat Sen University; State Key Lab Oncology South China; Netherlands Cancer Institute; Netherlands Cancer Institute; University of Amsterdam
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12511
• DOI: 10.1073/pnas.2417724121
• 发表日期: 2024-12-24
• 关键词: calcium; induction; stress; ros

摘要

Drugs that eliminate senescent cells, senolytics, can be powerful when combined with here SLC25A23 as a vulnerability of senescent cancer cells. Suppressing SLC25A23 disrupts cellular calcium homeostasis, impairs oxidative phosphorylation, and interferes with redox signaling, leading to death of senescent cells. These effects can be replicated by salinomycin, a cation ionophore antibiotic. Salinomycin prompts a pyroptosis- apoptosis- necroptosis (PAN)optosis- like cell death in senescent cells, including apoptosis and two forms of immunogenic cell death: necroptosis and pyroptosis. Notably, we observed that salinomycin treatment or SLC25A23 suppression elevates reactive oxygen species, upregulating death combination of a death receptor 5 (DR5) agonistic antibody and salinomycin is a robust senolytic cocktail. We provide evidence that this drug combination provokes a potent natural killer (NK) and CD8+ T cell-mediated immune destruction of senescent cancer cells, mediated by the pyroptotic cytokine interleukin 18 (IL18).