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剂）来增强其抗癌特性。然而，NDRG1 的确切作用仍存在争议，因为最新研究表明 NDRG1 也可以充当癌基因。我们课题组最近推出了线粒体靶向铁螯合剂去铁胺（mitoDFO）和地拉罗司（mitoDFX）作为有效的抗癌药物。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。我们证明这两种化合物特异性增加 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是由 GSK3α/β 介导的，导致 NDRG1 在 Thr346 处磷酸化，并在较小程度上在 Ser330 处磷酸化。 NDRG1 的缺失会增加 mitoDFX 诱导的细胞死亡。值得注意的是，缺乏 NDRG1 的 MDA-MB-231 细胞表现出细胞外酸化率降低，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 末端截短的亚型 (59112) 的过度表达显着降低了 ER 细胞对 mitoDFX 的敏感性。此外，过表达全长NDRG1的细胞表现出显着加速的肿瘤形成，而其N末端截短的亚型则表现出显着受损的形成肿瘤的能力。因此，全长 NDRG1 的过度表达可促进高度侵袭性三阴性乳腺癌中的肿瘤生长。版权所有 © 2024 Jadhav、Vondrackova、Potomova、Sandoval-Acuña、Smigova、Klanicova、Rosel、Brabek、Stursa、Werner 和 Truksa。

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.Copyright © 2024 Jadhav, Vondrackova, Potomova, Sandoval-Acuña, Smigova, Klanicova, Rosel, Brabek, Stursa, Werner and Truksa.