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.

中文翻译：

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靶向 prominin2 转录以克服癌症中的铁死亡抵抗

了解癌细胞如何抵抗铁死亡是一个重要问题，影响着将刺激铁死亡作为治疗策略的持续努力。我们报道了 prominin2 是由铁死亡刺激诱导的，并具有抵抗铁死亡的功能。尽管这一发现对治疗具有重要意义，但目前还没有特定的 prominin2 抑制剂。我们合理化了铁死亡应激诱导 prominin2 表达的机制，从而扩大了克服铁死亡抗性的选择范围。在这里，我们表明，4-羟基壬烯醛（4HNE）是一种由脂质过氧化产物形成的特定脂质代谢物，通过涉及 p38 MAP 激酶介导的 HSF1 激活和 PROM2 依赖于 HSF1 转录的机制刺激PROM2转录。HSF1 抑制剂使多种耐药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 抑制剂的组合会导致小鼠体内已形成肿瘤的细胞抑制，尽管单独治疗都无效。这些数据揭示了一种在癌症中诱导铁死亡的治疗新方法。