Division of Therapeutic Proteins, Office of Biotechnology Products, Center for Drug, Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
Mol Cancer Ther. 2010 Jun;9(6):1657-68. doi: 10.1158/1535-7163.MCT-09-0906. Epub 2010 Jun 1.
Rac1 GTPase regulates a variety of signaling pathways that are implicated in malignant phenotypes. Here, we show that selective inhibition of Rac1 activity by the pharmacologic inhibitor NSC23766 suppressed cell growth in a panel of human breast cancer cell lines, whereas it had little toxicity to normal mammary epithelial cells. NSC23766 elicits its cytotoxicity via two distinct mechanisms in a cell line-dependent manner: induction of G(1) cell cycle arrest in cell lines (MDA-MB-231, MCF7, and T47D) that express retinoblastoma (Rb) protein or apoptosis in Rb-deficient MDA-MB-468 cells. In MDA-MB-231 cells, Rac1 inhibition induced G(1) cell cycle arrest through downregulation of cyclin D1 and subsequent dephosphorylation/inactivation of Rb. By contrast, MDA-MB-468 cells underwent substantial apoptosis that was associated with loss of antiapoptotic proteins survivin and X-linked inhibitor of apoptosis protein (XIAP). Rac1 knockdown by RNAi interference confirmed the specificity of NSC23766 and requirement for Rac1 in the regulation of cyclin D1, survivin, and XIAP in breast cancer cells. Further, NF-kappaB, but not c-Jun NH(2)-terminal kinase or p38 pathways, mediates the survival signal from Rac1. Overall, our results indicate that Rac1 plays a central role in breast cancer cell survival through regulation of NF-kappaB-dependent gene products.
Rac1 GTPase 调节多种信号通路，这些信号通路与恶性表型有关。在这里，我们表明，通过药理学抑制剂 NSC23766 选择性抑制 Rac1 活性，抑制了一系列人类乳腺癌细胞系的细胞生长，而对正常乳腺上皮细胞几乎没有毒性。NSC23766 通过两种不同的机制以依赖细胞系的方式发挥其细胞毒性：在表达视网膜母细胞瘤 (Rb) 蛋白的细胞系（MDA-MB-231、MCF7 和 T47D）中诱导 G1 细胞周期停滞，或在 Rb 缺失的 MDA-MB-468 细胞中诱导细胞凋亡。在 MDA-MB-231 细胞中，Rac1 抑制通过下调细胞周期蛋白 D1 并随后使 Rb 去磷酸化/失活来诱导 G1 细胞周期停滞。相比之下，MDA-MB-468 细胞经历了大量的凋亡，这与抗凋亡蛋白 survivin 和 X 连锁凋亡抑制剂蛋白 (XIAP) 的丢失有关。RNAi 干扰的 Rac1 敲低证实了 NSC23766 的特异性以及 Rac1 在乳腺癌细胞中环细胞蛋白 D1、survivin 和 XIAP 调节中的必要性。此外，NF-kappaB 而不是 c-Jun NH2-末端激酶或 p38 途径介导 Rac1 的生存信号。总体而言，我们的结果表明 Rac1 通过调节 NF-kappaB 依赖性基因产物在乳腺癌细胞存活中发挥核心作用。
