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Low expression of ANT1 confers oncogenic properties to rhabdomyosarcoma tumor cells by modulating metabolism and death pathways.
Cell Death Discovery ( IF 6.1 ) Pub Date : 2020-07-24 , DOI: 10.1038/s41420-020-00302-1
J Vial 1 , P Huchedé 1 , S Fagault 1 , F Basset 1 , M Rossi 2 , J Geoffray 1 , H Soldati 3 , J Bisaccia 1 , M H Elsensohn 4 , M Creveaux 1 , D Neves 5 , J Y Blay 1 , F Fauvelle 6 , F Bouquet 7 , N Streichenberger 8, 9 , N Corradini 1 , C Bergeron 1 , D Maucort-Boulch 4 , P Castets 3 , M Carré 2 , K Weber 1 , M Castets 1
Affiliation  

Rhabdomyosarcoma (RMS) is the most frequent form of pediatric soft-tissue sarcoma. It is divided into two main subtypes: ERMS (embryonal) and ARMS (alveolar). Current treatments are based on chemotherapy, surgery, and radiotherapy. The 5-year survival rate has plateaued at 70% since 2000, despite several clinical trials. RMS cells are thought to derive from the muscle lineage. During development, myogenesis includes the expansion of muscle precursors, the elimination of those in excess by cell death and the differentiation of the remaining ones into myofibers. The notion that these processes may be hijacked by tumor cells to sustain their oncogenic transformation has emerged, with RMS being considered as the dark side of myogenesis. Thus, dissecting myogenic developmental programs could improve our understanding of RMS molecular etiology. We focused herein on ANT1, which is involved in myogenesis and is responsible for genetic disorders associated with muscle degeneration. ANT1 is a mitochondrial protein, which has a dual functionality, as it is involved both in metabolism via the regulation of ATP/ADP release from mitochondria and in regulated cell death as part of the mitochondrial permeability transition pore. Bioinformatics analyses of transcriptomic datasets revealed that ANT1 is expressed at low levels in RMS. Using the CRISPR-Cas9 technology, we showed that reduced ANT1 expression confers selective advantages to RMS cells in terms of proliferation and resistance to stress-induced death. These effects arise notably from an abnormal metabolic switch induced by ANT1 downregulation. Restoration of ANT1 expression using a Tet-On system is sufficient to prime tumor cells to death and to increase their sensitivity to chemotherapy. Based on our results, modulation of ANT1 expression and/or activity appears as an appealing therapeutic approach in RMS management.



中文翻译:

ANT1 的低表达通过调节代谢和死亡途径赋予横纹肌肉瘤肿瘤细胞致癌特性。

横纹肌肉瘤 (RMS) 是最常见的儿童软组织肉瘤。它分为两个主要亚型:ERMS(胚胎型)和 ARMS(肺泡型)。目前的治疗基于化疗、手术和放疗。尽管进行了多项临床试验,但自 2000 年以来,5 年生存率一直稳定在 70%。RMS 细胞被认为源自肌肉谱系。在发育过程中,肌生成包括肌肉前体的扩张、通过细胞死亡消除过量的前体以及剩余的分化为肌纤维。这些过程可能被肿瘤细胞劫持以维持其致癌转化的观点已经出现,RMS 被认为是肌生成的阴暗面。因此,剖析肌源性发育程序可以提高我们对 RMS 分子病因学的理解。我们在此重点关注 ANT1,它参与肌生成并负责与肌肉退化相关的遗传性疾病。ANT1 是一种线粒体蛋白,具有双重功能,因为它既通过调节线粒体 ATP/ADP 释放参与代谢,又作为线粒体通透性转换孔的一部分参与受调节的细胞死亡。转录组数据集的生物信息学分析表明,ANT1 在 RMS 中表达水平较低。使用 CRISPR-Cas9 技术,我们发现 ANT1 表达减少赋予 RMS 细胞在增殖和抵抗应激诱导死亡方面的选择性优势。这些影响主要是由 ANT1 下调引起的异常代谢转换引起的。使用 Tet-On 系统恢复 ANT1 表达足以促使肿瘤细胞死亡并增加其对化疗的敏感性。根据我们的结果,ANT1 表达和/或活性的调节似乎是 RMS 管理中一种有吸引力的治疗方法。

更新日期:2020-07-24
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