Arumugam Arunkumar, Subramani Ramadevi, Lakshmanaswamy Rajkumar
Center of Emphasis in Cancer Research, Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA.
Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA.
Mol Ther Oncolytics. 2021 Feb 24;20:596-606. doi: 10.1016/j.omto.2021.02.014. eCollection 2021 Mar 26.
Triple-negative breast cancers (TNBCs) are aggressive cancers, which currently do not have effective treatment options. Migration and establishment of metastatic colonies require dynamic cytoskeletal modifications characterized by polymerization and depolymerization of actin. Studies have demonstrated a direct molecular link between the integrin-focal adhesion kinase (FAK) pathway and cytoskeletal modifications. Nimbolide, a major bioactive compound present in neem leaves, shows promising anti-cancer effect on various cancers. In this study, we have demonstrated the growth and metastasis inhibitory potential of nimbolide on TNBC cells. Nimbolide inhibited cell proliferation, migratory, and invasive abilities of TNBC cells and also changed the shape of MDA-MB-231 cells, which is correlated with cytoskeletal changes including actin depolymerization. Furthermore, analysis revealed that integrins αV and β3, ILK, FAK, and PAK levels were downregulated by nimbolide. Even in cells where Rac1/Cdc42 was constitutively activated, nimbolide inhibited the formation of filopodial structures. Immunofluorescence analysis of phosphorylated p21 activated kinase (pPAK) showed reduced expression in nimbolide-treated cells. Nimbolide significantly reduced the metastatic colony formation in lung, liver, and brain of athymic nude mice. In conclusion, our data demonstrate that nimbolide inhibits TNBC by altering the integrin and FAK signaling pathway.
三阴性乳腺癌（TNBC）是侵袭性癌症，目前尚无有效的治疗方案。转移瘤的迁移和形成需要动态的细胞骨架修饰，其特征是肌动蛋白的聚合和解聚。研究表明，整合素-黏着斑激酶（FAK）信号通路与细胞骨架修饰之间存在直接的分子联系。印楝素是印楝叶中的一种主要生物活性化合物，对多种癌症显示出有前景的抗癌作用。在本研究中，我们证明了印楝素对TNBC细胞具有生长和转移抑制潜力。印楝素抑制TNBC细胞的增殖、迁移和侵袭能力，还改变了MDA-MB-231细胞的形态，这与包括肌动蛋白解聚在内的细胞骨架变化相关。此外，分析显示印楝素下调了整合素αV和β3、整合素连接激酶（ILK）、FAK和p21激活激酶（PAK）的水平。即使在Rac1/Cdc42组成性激活的细胞中，印楝素也抑制丝状伪足结构的形成。磷酸化p21激活激酶（pPAK）的免疫荧光分析显示，在印楝素处理的细胞中其表达降低。印楝素显著减少了无胸腺裸鼠肺、肝和脑中转移瘤的形成。总之，我们的数据表明印楝素通过改变整合素和FAK信号通路来抑制TNBC。
