Jochems Fleur, Baltira Chrysiida, MacDonald Julie A, Daniels Veerle, Mathur Abhijeet, de Gooijer Mark C, van Tellingen Olaf, Letai Anthony, Bernards René
Division of Molecular Carcinogenesis, Oncode Institute, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.
Division of Pharmacology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.
Cell Death Differ. 2025 May;32(5):855-865. doi: 10.1038/s41418-024-01439-7. Epub 2024 Dec 21.
Cellular senescence is a stress response that cells can employ to resist cell death. Senescent cells rely on anti-apoptotic signaling for their survival, which can be targeted by senolytic agents, like the BCL-XL, BCL-2, BCL-W inhibitor ABT-263. However, the response to ABT-263 of senescent cancer cells ranges from highly sensitive to refractory. Using BH3 profiling, we identify here apoptotic blocks in cancer cells that are resistant to this senolytic treatment and discover a correlation between mitochondrial apoptotic priming and cellular sensitivity to ABT-263 in senescence. Intriguingly, ABT-263 sensitivity correlates with overall mitochondrial apoptotic priming, not only in senescence but also in the parental state. Moreover, we confirm that ABT-263 exposure increases dependency on MCL-1, which is most enhanced in ABT-263 sensitive cells. ABT-263 resistant cells however upregulate MCL-1, while sensitive cells exhibit low levels of this anti-apoptotic protein. Overall, our data indicate that the response of senescent cells to ABT-263 is predetermined by the mitochondrial apoptotic priming state of the parental cells, which could serve as a predictive biomarker for response to senolytic therapy.
细胞衰老 是一种应激反应，细胞可借此来抵抗细胞死亡。衰老细胞依靠抗凋亡信号来存活，而衰老细胞溶解剂（如BCL-XL、BCL-2、BCL-W抑制剂ABT-263）可作用于这些抗凋亡信号。然而，衰老癌细胞对ABT-263的反应程度从高度敏感到难治不等。通过BH3分析，我们在此确定了对这种衰老细胞溶解治疗有抗性的癌细胞中的凋亡阻滞，并发现衰老过程中线粒体凋亡启动与细胞对ABT-263的敏感性之间存在关联。有趣的是，ABT-263敏感性不仅在衰老细胞中，而且在亲代状态下都与整体线粒体凋亡启动相关。此外，我们证实ABT-263处理会增加细胞对MCL-1的依赖性，这在ABT-263敏感细胞中增强最为明显。然而，ABT-263抗性细胞会上调MCL-1，而敏感细胞中这种抗凋亡蛋白的水平较低。总体而言，我们的数据表明，衰老细胞对ABT-263的反应由亲代细胞的线粒体凋亡启动状态预先决定，这可作为衰老细胞溶解疗法反应的预测生物标志物。
