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Fenretinide induces a new form of dynamin-dependent cell death in pediatric sarcoma.
Cell Death and Differentiation ( IF 12.4 ) Pub Date : 2020-03-06 , DOI: 10.1038/s41418-020-0518-z
Eva Brack 1 , Marco Wachtel 1 , Anja Wolf 1 , Andres Kaech 2 , Urs Ziegler 2 , Beat W Schäfer 1
Affiliation  

Alveolar rhabdomyosarcoma (aRMS) is a highly malicious childhood malignancy characterized by specific chromosomal translocations mostly encoding the oncogenic transcription factor PAX3-FOXO1 and therefore also referred to as fusion-positive RMS (FP-RMS). Previously, we have identified fenretinide (retinoic acid p-hydroxyanilide) to affect PAX3-FOXO1 expression levels as well as FP-RMS cell viability. Here, we characterize the mode of action of fenretinide in more detail. First, we demonstrate that fenretinide-induced generation of reactive oxygen species (ROS) depends on complex II of the mitochondrial respiratory chain, since ROS scavenging as well as complexing of iron completely abolished cell death. Second, we co-treated cells with a range of pharmacological inhibitors of specific cell death pathways including z-vad (apoptosis), necrostatin-1 (necroptosis), 3-methyladenine (3-MA) (autophagy), and ferrostatin-1 (ferroptosis) together with fenretinide. Surprisingly, none of these inhibitors was able to prevent cell death. Also genetic depletion of key players in the apoptotic and necroptotic pathway (BAK, BAX, and RIPK1) confirmed the pharmacological data. Interestingly however, electron microscopy of fenretinide-treated cells revealed an excessive accumulation of cytoplasmic vacuoles, which were distinct from autophagosomes. Further flow cytometry and fluorescence microscopy experiments suggested a hyperstimulation of macropinocytosis, leading to an accumulation of enlarged early and late endosomes. Surprisingly, pharmacological inhibition as well as genetic depletion of large dynamin GTPases completely abolished fenretinide-induced vesicle formation and subsequent cell death, suggesting a new form of dynamin-dependent programmed cell death. Taken together, our data identify a new form of cell death mediated through the production of ROS by fenretinide treatment, highlighting the value of this compound for treatment of sarcoma patients including FP-RMS.

中文翻译:

芬维A胺在小儿肉瘤中诱导一种新形式的动力蛋白依赖性细胞死亡。

肺泡横纹肌肉瘤 (aRMS) 是一种高度恶意的儿童恶性肿瘤,其特征在于特定的染色体易位,主要编码致癌转录因子 PAX3-FOXO1,因此也称为融合阳性 RMS (FP-RMS)。以前,我们已经确定芬维A胺(视黄酸对羟基苯胺)影响 PAX3-FOXO1 表达水平以及 FP-RMS 细胞活力。在这里,我们更详细地描述了芬维A胺的作用模式。首先,我们证明芬维A胺诱导的活性氧(ROS)的产生取决于线粒体呼吸链的复合物II,因为ROS清除以及铁的复合完全消除了细胞死亡。其次,我们用一系列特定细胞死亡途径的药理学抑制剂共同处理细胞,包括 z-vad(细胞凋亡)、necrostatin-1(坏死性凋亡)、3-甲基腺嘌呤 (3-MA)(自噬)和 ferrostatin-1(ferroptosis)以及芬维A胺。令人惊讶的是,这些抑制剂都不能阻止细胞死亡。凋亡和坏死性凋亡途径(BAK、BAX 和 RIPK1)中关键参与者的遗传耗竭也证实了药理学数据。然而,有趣的是,芬维A胺处理细胞的电子显微镜显示细胞质液泡的过度积累,这与自噬体不同。进一步的流式细胞术和荧光显微镜实验表明巨胞饮作用过度刺激,导致早期和晚期内体增大的积累。出奇,药理抑制以及大动力蛋白 GTP 酶的遗传耗竭完全消除了芬维A 胺诱导的囊泡形成和随后的细胞死亡,表明了一种新的动力蛋白依赖性程序性细胞死亡形式。总之,我们的数据确定了一种通过芬维A胺治疗产生 ROS 介导的新形式的细胞死亡,突出了这种化合物在治疗肉瘤患者(包括 FP-RMS)方面的价值。
更新日期:2020-04-24
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