Metadherin enhances vulnerability of cancer cells to ferroptosis
Metadherin enhances vulnerability of cancer cells to ferroptosis
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DOI：
10.1038/s41419-019-1897-2
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发表时间：
2019-09-17
影响因子：
9
通讯作者：
Meng, Xiangbing
中科院分区：
文献类型：
--
作者：
Bi, Jianling;Yang, Shujie;Meng, Xiangbing
铁凋亡是一种铁依赖性、非凋亡形式的受调节的细胞死亡，由生物膜内的脂质氢过氧化物驱动。尽管耐药间充质高癌特别容易受到铁凋亡诱导剂，特别是磷脂谷胱甘肽过氧化物酶4（GPx 4）抑制剂的影响，但其潜在机制尚未被破译。因此，GPx 4抑制剂在癌症治疗中的充分应用仍然具有挑战性。在这里，我们证明，metadherin（MTDH）赋予治疗抗性间充质高细胞状态和增强的敏感性，诱导铁凋亡。在机制上，MTDH在信使RNA和蛋白质水平上抑制GPx 4以及溶质载体家族3成员2（SLC 3A 2，系统X-c（-）异源二聚化伴侣）。我们的代谢组学研究表明，MTDH减少细胞内半胱氨酸，但增加谷氨酸水平，最终降低谷胱甘肽水平，并为铁凋亡的脆弱性增加奠定基础。最后，我们观察到增强的抗肿瘤作用，当我们结合各种铁凋亡诱导剂在体外和体内; MTDH的水平与铁凋亡的效果。我们首次证明了MTDH增强了癌细胞对铁凋亡的脆弱性，并可能作为未来以铁凋亡为中心的癌症治疗的治疗生物标志物。
Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death driven by lipid hydroperoxides within biological membranes. Although therapy-resistant mesenchymal-high cancers are particularly vulnerable to ferroptosis inducers, especially phospholipid glutathione peroxidase 4 (GPx4) inhibitors, the underlying mechanism is yet to be deciphered. As such, the full application of GPx4 inhibitors in cancer therapy remains challenging. Here we demonstrate that metadherin (MTDH) confers a therapy-resistant mesenchymal-high cell state and enhanced sensitivity to inducers of ferroptosis. Mechanistically, MTDH inhibited GPx4, as well as the solute carrier family 3 member 2 (SLC3A2, a system X-c(-) heterodimerization partner), at both the messenger RNA and protein levels. Our metabolomic studies demonstrated that MTDH reduced intracellular cysteine, but increased glutamate levels, ultimately decreasing levels of glutathione and setting the stage for increased vulnerability to ferroptosis. Finally, we observed an enhanced antitumor effect when we combined various ferroptosis inducers both in vitro and in vivo; the level of MTDH correlated with the ferroptotic effect. We have demonstrated for the first time that MTDH enhances the vulnerability of cancer cells to ferroptosis and may serve as a therapeutic biomarker for future ferroptosis-centered cancer therapy.