Casagrande Raffi Gabriele, 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
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands.
State Key Laboratory of Oncology in South China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Proc Natl Acad Sci U S A. 2024 Dec 24;121(52):e2417724121. doi: 10.1073/pnas.2417724121. Epub 2024 Dec 18.
Drugs that eliminate senescent cells, senolytics, can be powerful when combined with prosenescence cancer therapies. Using a CRISPR/Cas9-based genetic screen, we identify 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 receptor 5 via Jun N-terminal protein kinase (JNK) pathway activation. We show that a 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).
清除衰老细胞的药物（衰老细胞溶解剂）与促衰老癌症疗法联合使用时可能会产生强大效果。通过基于CRISPR/Cas9的基因筛选，我们在此确定SLC25A23是衰老癌细胞的一个脆弱靶点。抑制SLC25A23会破坏细胞钙稳态，损害氧化磷酸化，并干扰氧化还原信号传导，导致衰老细胞死亡。这些效应可被盐霉素（一种阳离子离子载体抗生素）复制。盐霉素促使衰老细胞发生一种类似于焦亡-凋亡-坏死性凋亡（PAN）的细胞死亡，包括凋亡以及两种形式的免疫原性细胞死亡：坏死性凋亡和焦亡。值得注意的是，我们观察到盐霉素处理或SLC25A23抑制会升高活性氧水平，通过激活Jun N端蛋白激酶（JNK）途径上调死亡受体5。我们表明，死亡受体5（DR5）激动性抗体与盐霉素的组合是一种强大的衰老细胞溶解鸡尾酒疗法。我们提供的证据表明，这种药物组合会引发由焦亡细胞因子白细胞介素18（IL18）介导的强大的自然杀伤（NK）细胞和CD8 + T细胞介导的衰老癌细胞免疫破坏。
