Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.
Department of Oncology and Laboratory Medicine, Yamaguchi University, Graduate School of Medicine, Ube, Yamaguchi, Japan.
BMC Cancer. 2020 Jul 22;20(1):681. doi: 10.1186/s12885-020-07167-8.
Iron is required for cellular metabolism, and rapidly proliferating cancer cells require more of this essential nutrient. Therefore, iron regulation may well represent a new avenue for cancer therapy. We have reported, through in vitro and in vivo research involving pancreatic cancer cell lines, that the internal-use, next-generation iron chelator deferasirox (DFX) exhibits concentration-dependent tumour-suppressive effects, among other effects. After performing a microarray analysis on the tumour grafts used in that research, we found that DFX may be able to suppress the cellular movement pathways of pancreatic cancer cells. In this study, we conducted in vitro analyses to evaluate the effects of DFX on the invasive and migratory abilities of pancreatic cancer cells.
We used pancreatic cancer cell lines (BxPC-3, Panc-1, and HPAF II) to examine the efficacy of DFX in preventing invasion in vitro, evaluated using scratch assays and Boyden chamber assays. In an effort to understand the mechanism of action whereby DFX suppresses tumour invasion and migration, we performed G-LISA to examine the activation of Cdc42 and Rac1 which are known for their involvement in cellular movement pathways.
In our scratch assays, we observed that DFX-treated cells had significantly reduced invasive ability compared with that of control cells. Similarly, in our Boyden chamber assays, we observed that DFX-treated cells had significantly reduced migratory ability. After analysis of the Rho family of proteins, we observed a significant reduction in the activation of Cdc42 and Rac1 in DFX-treated cells.
DFX can suppress the motility of cancer cells by reducing Cdc42 and Rac1 activation. Pancreatic cancers often have metastatic lesions, which means that use of DFX will suppress not only tumour proliferation but also tumour invasion, and we expect that this will lead to improved prognoses.
铁是细胞代谢所必需的，而快速增殖的癌细胞需要更多这种必需的营养物质。因此，铁的调节很可能代表癌症治疗的新途径。我们通过涉及胰腺癌细胞系的体外和体内研究报告说，内用第二代铁螯合剂地拉罗司（DFX）除了其他作用外，还具有浓度依赖性的肿瘤抑制作用。在对该研究中使用的肿瘤移植物进行微阵列分析后，我们发现 DFX 可能能够抑制胰腺癌细胞的细胞运动途径。在这项研究中，我们进行了体外分析，以评估 DFX 对胰腺癌细胞侵袭和迁移能力的影响。
我们使用胰腺癌细胞系（BxPC-3、Panc-1 和 HPAF II）来研究 DFX 在体外预防侵袭的效果，使用划痕实验和 Boyden 室实验进行评估。为了了解 DFX 抑制肿瘤侵袭和迁移的作用机制，我们进行了 G-LISA 实验，以检查已知参与细胞运动途径的 Cdc42 和 Rac1 的激活。
在我们的划痕实验中，我们观察到 DFX 处理的细胞的侵袭能力明显低于对照细胞。同样，在我们的 Boyden 室实验中，我们观察到 DFX 处理的细胞的迁移能力明显降低。在分析 Rho 家族蛋白后，我们观察到 DFX 处理的细胞中 Cdc42 和 Rac1 的激活显著降低。
DFX 通过减少 Cdc42 和 Rac1 的激活来抑制癌细胞的运动能力。胰腺癌通常有转移性病变，这意味着使用 DFX 将不仅抑制肿瘤增殖，而且还抑制肿瘤侵袭，我们预计这将改善预后。
