Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
EMBO Mol Med. 2021 Aug 9;13(8):e13792. doi: 10.15252/emmm.202013792. Epub 2021 Jul 5.
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.
了解癌细胞如何抵抗铁死亡是一个重大问题，这影响了将铁死亡作为治疗策略进行的持续努力。我们报告称，顶体蛋白 2 是由铁死亡刺激诱导的，并具有抵抗铁死亡的作用。尽管这一发现对治疗具有重要意义，但目前还没有专门的顶体蛋白 2 抑制剂。我们推断，铁死亡应激诱导顶体蛋白 2 表达的机制可以作为靶点，从而扩大克服铁死亡耐药性的选择范围。在这里，我们表明，4-羟基壬烯醛（4-HNE），一种特定的脂质代谢物，是由脂质过氧化产物形成的，通过一种涉及 p38 MAP 激酶介导的 HSF1 激活和 HSF1 依赖的 PROM2 转录的机制来刺激 PROM2 转录。HSF1 抑制剂可使多种耐药性癌细胞对诱导铁死亡的药物敏感。重要的是，铁死亡诱导药物和 HSF1 抑制剂的联合使用可导致小鼠体内已建立的肿瘤的细胞停滞，尽管单独使用任何一种药物都没有效果。这些数据揭示了一种在癌症中诱导铁死亡的新治疗方法。
