Targeting prominin2 transcription to overcome ferroptosis resistance in cancer.
Targeting prominin2 transcription to overcome ferroptosis resistance in cancer.
复制标题
靶向显著蛋白2转录以克服癌症中铁下垂抵抗。
DOI：
10.15252/emmm.202013792
复制
发表时间：
2021-08-09
影响因子：
11.1
通讯作者：
Mercurio AM
中科院分区：
文献类型：
--
作者：
Brown CW;Chhoy P;Mukhopadhyay D;Karner ER;Mercurio AM
了解癌细胞如何抵抗铁性下垂是一个重要的问题，它影响到正在进行的刺激铁性下垂作为一种治疗策略的努力。我们报道了显著蛋白2是由铁性下垂刺激诱导的，并具有抵抗铁性下垂死亡的功能。尽管这一发现对治疗有重大意义，但尚不能获得特定的显著蛋白2抑制剂。我们合理地认为，铁下垂应激诱导显著蛋白2表达的机制是有针对性的，从而扩大了克服铁下垂抵抗的选择范围。在这里，我们证明了脂质过氧化产物4-羟基壬烯醛(4HNE)通过p38 MAP激酶介导的HSF1激活和HSF1依赖的PROM2转录刺激PROM2转录。HSF1抑制剂使多种耐药癌细胞对引起铁性下垂的药物敏感。重要的是，一种诱导铁下垂的药物和一种HSF1抑制剂的组合导致了小鼠已建立的肿瘤的细胞抑制，尽管单独治疗都不是有效的。这些数据揭示了一种治疗癌症铁性下垂的新方法。刺激性铁下垂已成为一种潜在的抗癌治疗策略。然而，一些肿瘤细胞对已知的铁下垂刺激具有抵抗力。这项研究确定了导致铁性上睑下垂的机制，并制定了克服耐药性的策略。
Understanding how cancer cells resist ferroptosis is a significant problem that impacts ongoing efforts to stimulate ferroptosis as a therapeutic strategy. We reported that prominin2 is induced by ferroptotic stimuli and functions to resist ferroptotic death. Although this finding has significant implications for therapy, specific prominin2 inhibitors are not available. We rationalized that the mechanism by which prominin2 expression is induced by ferroptotic stress could be targeted, expanding the range of options to overcome ferroptosis resistance. Here, we show that that 4‐hydroxynonenal (4HNE), a specific lipid metabolite formed from the products of lipid peroxidation stimulates PROM2 transcription by a mechanism that involves p38 MAP kinase‐mediated activation of HSF1 and HSF1‐dependent transcription of PROM2. HSF1 inhibitors sensitize a wide variety of resistant cancer cells to drugs that induce ferroptosis. Importantly, the combination of a ferroptosis‐inducing drug and an HSF1 inhibitor causes the cytostasis of established tumors in mice, although neither treatment alone is effective. These data reveal a novel approach for the therapeutic induction of ferroptosis in cancer. Stimulating ferroptosis has emerged as a potential therapeutic strategy against cancer. Some tumor cells, however, are resistant to known ferroptosis stimuli. This study identifies mechanisms that contribute to ferroptosis and develops strategies to overcome resistance.