PDF(Pubmed)
Abstract：
Multiple studies indicate that iron chelators enhance their anti-cancer properties by inducing NDRG1, a known tumor and metastasis suppressor. However, the exact role of NDRG1 remains controversial, as newer studies have shown that NDRG1 can also act as an oncogene. Our group recently introduced mitochondrially targeted iron chelators deferoxamine (mitoDFO) and deferasirox (mitoDFX) as effective anti-cancer agents. In this study, we evaluated the ability of these modified chelators to induce NDRG1 and the role of NDRG1 in breast cancer. We demonstrated that both compounds specifically increase NDRG1 without inducing other NDRG family members. We have documented that the effect of mitochondrially targeted chelators is at least partially mediated by GSK3α/β, leading to phosphorylation of NDRG1 at Thr346 and to a lesser extent on Ser330. Loss of NDRG1 increases cell death induced by mitoDFX. Notably, MDA-MB-231 cells lacking NDRG1 exhibit reduced extracellular acidification rate and grow slower than parental cells, while the opposite is true for ER+ MCF7 cells. Moreover, overexpression of full-length NDRG1 and the N-terminally truncated isoform (59112) significantly reduced sensitivity towards mitoDFX in ER+ cells. Furthermore, cells overexpressing full-length NDRG1 exhibited a significantly accelerated tumor formation, while its N-terminally truncated isoforms showed significantly impaired capacity to form tumors. Thus, overexpression of full-length NDRG1 promotes tumor growth in highly aggressive triple-negative breast cancer.
摘要：
多项研究表明，铁螯合剂通过诱导NDRG1（一种已知的肿瘤和转移抑制因子）来增强其抗癌特性。然而,NDRG1的确切作用仍然存在争议，新的研究表明，NDRG1也可以作为癌基因。我们小组最近引入了线粒体靶向铁螯合剂去铁胺（mitoDFO）和地拉罗司（mitoDFX）作为有效的抗癌剂。在这项研究中,我们评估了这些修饰的螯合剂诱导NDRG1的能力以及NDRG1在乳腺癌中的作用.我们证明了两种化合物均特异性增加NDRG1而不诱导其他NDRG家族成员。我们已经证明，线粒体靶向螯合剂的作用至少部分由GSK3α/β介导，导致NDRG1在Thr346磷酸化，而在Ser330上则较小。NDRG1的缺失增加了mitoDFX诱导的细胞死亡。值得注意的是,缺乏NDRG1的MDA-MB-231细胞表现出降低的细胞外酸化速率，并且生长速度比亲本细胞慢。而ER+MCF7细胞则相反。此外，全长NDRG1和N末端截短的同种型（59112）的过表达显着降低了ER细胞对mitoDFX的敏感性。此外，过表达全长NDRG1的细胞表现出明显加速的肿瘤形成，而其N末端截短的同工型显示出显着受损的形成肿瘤的能力。因此，在高度侵袭性的三阴性乳腺癌中,全长NDRG1的过表达促进肿瘤生长.
