PDF(Pubmed)
Abstract：
Caspase-9, a cysteine-aspartate protease traditionally associated with intrinsic apoptosis, has recently emerged as having non-apoptotic roles, including influencing cell migration-an aspect that has received limited attention in existing studies. In our investigation, we aimed to explore the impact of caspase-9 on the migration and invasion behaviors of MDA-MB-231, a triple-negative breast cancer (TNBC) cell line known for its metastatic properties. We established a stable cell line expressing an inducible caspase-9 (iC9) in MDA-MB-231 and assessed their metastatic behavior using both monolayer and the 3D organotypic model in co-culture with human Foreskin fibroblasts (HFF). Our findings revealed that caspase-9 had an inhibitory effect on migration and invasion in both models. In monolayer culture, caspase-9 effectively suppressed the migration and invasion of MDA-MB-231 cells, comparable to the anti-metastatic agent panitumumab (Pan). Notably, the combination of caspase-9 and Pan exhibited a significant additional effect in reducing metastatic behavior. Interestingly, caspase-9 demonstrated superior efficacy compared to Pan in the organotypic model. Molecular analysis showed down regulation of epithelial-mesenchymal transition and migratory markers, in caspase-9 activated cells. Additionally, flow cytometry analysis indicated a cell cycle arrest. Moreover, pre-treatment with activated caspase-9 sensitized cells to the chemotherapy of doxorubicin, thereby enhancing its effectiveness. In conclusion, the anti-metastatic potential of caspase-9 presents avenues for the development of novel therapeutic approaches for TNBC/metastatic breast cancer. Although more studies need to figure out the exact involving mechanisms behind this behavior.
摘要：
Caspase-9，一种传统上与内在凋亡相关的半胱氨酸-天冬氨酸蛋白酶，最近出现了非凋亡作用，包括影响细胞迁移-一个在现有研究中受到有限关注的方面。在我们的调查中,我们旨在探讨caspase-9对MDA-MB-231迁移和侵袭行为的影响,MDA-MB-231是一种以转移特性而闻名的三阴性乳腺癌(TNBC)细胞系.我们在MDA-MB-231中建立了表达诱导型caspase-9（iC9）的稳定细胞系，并使用单层和3D器官型模型在与人Foreskin成纤维细胞（HFF）的共培养中评估了它们的转移行为。我们的发现表明caspase-9对两种模型的迁移和侵袭都有抑制作用。在单层培养中,caspase-9能有效抑制MDA-MB-231细胞的迁移和侵袭,与抗转移剂帕尼单抗（Pan）相当。值得注意的是,caspase-9和Pan的组合在减少转移行为方面表现出显著的额外作用。有趣的是,caspase-9在器官型模型中与Pan相比表现出优异的功效。分子分析显示上皮-间质转化和迁移标志物下调，在caspase-9激活的细胞中。此外,流式细胞术分析表明细胞周期停滞。此外，用活化的caspase-9致敏细胞预处理阿霉素的化疗，从而提高其有效性。总之,caspase-9的抗转移潜力为开发TNBC/转移性乳腺癌的新治疗方法提供了途径。虽然更多的研究需要弄清楚这种行为背后的确切机制。
