Aldo-keto reductases protect metastatic melanoma from ER stress-independent ferroptosis
Aldo-keto reductases protect metastatic melanoma from ER stress-independent ferroptosis
复制标题
DOI：
10.1038/s41419-019-2143-7
复制
发表时间：
2019-11-28
影响因子：
9
通讯作者：
Corazzari, Marco
中科院分区：
文献类型：
--
作者：
Gagliardi, Mara;Cotella, Diego;Corazzari, Marco
近年来，黑色素瘤的发病率不断增加，预后仍然很差，并且缺乏能够保证患者充分生存的治愈方法。尽管新的基于免疫的偶联靶向治疗策略令人鼓舞，但靶向/交叉耐药性和/或副作用（如自身免疫性疾病）的出现可能限制其临床应用。因此，迫切需要替代的治疗策略来有效地杀死黑素瘤细胞。在转移来源的野生型和致癌BRAF黑色素瘤细胞中评价了铁凋亡的诱导和执行，并且已经在分子水平上剖析了负责抗性的过程。虽然有效地诱导在所有细胞中，在致癌BRAF和ER应激独立的方式，大多数细胞耐铁凋亡执行。在分子水平上，我们发现：抗性细胞有效地激活NRF 2，NRF 2又以ER应激非依赖性方式上调早期铁凋亡标志物CHAC 1，并且醛酮还原酶AKR 1C 1除以3，其降解12/15-LOX产生的脂质过氧化物，从而导致铁凋亡细胞死亡抗性。然而，抑制AKR活性/表达完全使抗性黑素瘤细胞对铁凋亡执行重新敏感。最后，我们发现与黑色素瘤细胞分化相关的铁敏感性不能应用于转移源性细胞，这是由于EMT相关的基因表达重编程过程。然而，我们确定了SCL 7A 11作为一个有价值的标志物来预测转移性黑色素瘤细胞对铁凋亡的易感性。我们的研究结果确定了使用亲铁蛋白药物偶联AKR抑制剂作为一种新的有价值的策略，有效地杀死人类皮肤黑色素瘤细胞。
The incidence of melanoma is increasing over the years with a still poor prognosis and the lack of a cure able to guarantee an adequate survival of patients. Although the new immuno-based coupled to target therapeutic strategy is encouraging, the appearance of targeted/cross-resistance and/or side effects such as autoimmune disorders could limit its clinical use. Alternative therapeutic strategies are therefore urgently needed to efficiently kill melanoma cells. Ferroptosis induction and execution were evaluated in metastasis-derived wild-type and oncogenic BRAF melanoma cells, and the process responsible for the resistance has been dissected at molecular level. Although efficiently induced in all cells, in an oncogenic BRAF- and ER stress-independent way, most cells were resistant to ferroptosis execution. At molecular level we found that: resistant cells efficiently activate NRF2 which in turn upregulates the early ferroptotic marker CHAC1, in an ER stress-independent manner, and the aldo-keto reductases AKR1C1 divided by 3 which degrades the 12/15-LOX-generated lipid peroxides thus resulting in ferroptotic cell death resistance. However, inhibiting AKRs activity/expression completely resensitizes resistant melanoma cells to ferroptosis execution. Finally, we found that the ferroptotic susceptibility associated with the differentiation of melanoma cells cannot be applied to metastatic-derived cells, due to the EMT-associated gene expression reprogramming process. However, we identified SCL7A11 as a valuable marker to predict the susceptibility of metastatic melanoma cells to ferroptosis. Our results identify the use of pro-ferroptotic drugs coupled to AKRs inhibitors as a new valuable strategy to efficiently kill human skin melanoma cells.