研究发现，活化的 caspase-3 倾向于诱导 Gasdermin E (GSDME) 缺陷细胞凋亡，但在 GSDME 充足的细胞中诱导细胞焦亡。胰腺导管腺癌 (PDAC) 细胞的高 GSDME 表达和凋亡抗性揭示了通过促进细胞焦亡来治疗 PDAC 的另一种有吸引力的策略。在这里，我们报告了一个 hGLuc-hGSDME-PCA 系统，用于针对 PDAC 潜在 GSDME 激活剂的高通量筛选。该筛选系统巧妙地量化了 GSDME-N 的寡聚化，以表征化疗药物刺激下是否发生细胞焦亡。基于该系统，从FDA批准的包含106个化合物的抗癌药物库中筛选出了ponatinib和perifosine。具体来说，它们表现出最有效的发光活性，并导致 PDAC 细胞剧烈焦亡。此外，我们在体外和体内证明，哌立福辛通过 caspase-3/GSDME 途径促进焦亡，从而抑制胰腺癌。总的来说，这项研究揭示了 hGLuc-hGSDME-PCA 在识别触发 GSDME 依赖性细胞焦亡的化合物和开发有前景的 PDAC 治疗药物方面具有重要意义。© 2023 中国药学会和中国医学科学院药物研究所。由 Elsevier B.V. 制作和主持

It is discovered that activated caspase-3 tends to induce apoptosis in gasdermin E (GSDME)-deficient cells, but pyroptosis in GSDME-sufficient cells. The high GSDME expression and apoptosis resistance of pancreatic ductal adenocarcinoma (PDAC) cells shed light on another attractive strategy for PDAC treatment by promoting pyroptosis. Here we report a hGLuc-hGSDME-PCA system for high-throughput screening of potential GSDME activators against PDAC. This screening system neatly quantifies the oligomerization of GSDME-N to characterize whether pyroptosis occurs under the stimulation of chemotherapy drugs. Based on this system, ponatinib and perifosine are screened out from the FDA-approved anti-cancer drug library containing 106 compounds. Concretely, they exhibit the most potent luminescent activity and cause drastic pyroptosis in PDAC cells. Further, we demonstrate that perifosine suppresses pancreatic cancer by promoting pyroptosis via caspase-3/GSDME pathway both in vitro and in vivo. Collectively, this study reveals the great significance of hGLuc-hGSDME-PCA in identifying compounds triggering GSDME-dependent pyroptosis and developing promising therapeutic agents for PDAC.© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.