Department of Anesthesiology, School of Medicine, Yale University, New Haven, CT, 06519, USA.
Humacyte Inc., Durham, NC, 27213, USA.
Cell Death Dis. 2024 Jun 22;15(6):440. doi: 10.1038/s41419-024-06822-3.
The transmembrane death receptor Fas transduces apoptotic signals upon binding its ligand, FasL. Although Fas is highly expressed in cancer cells, insufficient cell surface Fas expression desensitizes cancer cells to Fas-induced apoptosis. Here, we show that the increase in Fas microaggregate formation on the plasma membrane in response to the inhibition of endocytosis sensitizes cancer cells to Fas-induced apoptosis. We used a clinically accessible Rho-kinase inhibitor, fasudil, that reduces endocytosis dynamics by increasing plasma membrane tension. In combination with exogenous soluble FasL (sFasL), fasudil promoted cancer cell apoptosis, but this collaborative effect was substantially weaker in nonmalignant cells. The combination of sFasL and fasudil prevented glioblastoma cell growth in embryonic stem cell-derived brain organoids and induced tumor regression in a xenograft mouse model. Our results demonstrate that sFasL has strong potential for apoptosis-directed cancer therapy when Fas microaggregate formation is augmented by mechano-inhibition of endocytosis.
跨膜死亡受体 Fas 在与其配体 FasL 结合后传递凋亡信号。虽然 Fas 在癌细胞中高度表达，但细胞表面 Fas 表达不足会使癌细胞对 Fas 诱导的凋亡产生抗药性。在这里，我们发现，在细胞内吞作用受到抑制时，Fas 在质膜上形成微聚集体的增加使癌细胞对 Fas 诱导的凋亡敏感。我们使用了一种临床可用的 Rho 激酶抑制剂 fasudil，它通过增加质膜张力来减少内吞作用的动力学。fasudil 与外源性可溶性 FasL（sFasL）联合使用可促进癌细胞凋亡，但在非恶性细胞中，这种协同作用要弱得多。sFasL 和 fasudil 的联合使用可防止胚胎干细胞衍生的脑类器官中的神经胶质瘤细胞生长，并在异种移植小鼠模型中诱导肿瘤消退。我们的研究结果表明，当 Fas 微聚集体的形成通过内吞作用的力学抑制得到增强时，sFasL 具有很强的用于凋亡导向癌症治疗的潜力。
